Imidazopyrazines as protein kinase inhibitors

ABSTRACT

In its many embodiments, the present invention provides a novel class of imidazopyrazine compounds as inhibitors of protein and/or checkpoint kinases, methods of preparing such compounds, pharmaceutical compositions including one or more such compounds, methods of preparing pharmaceutical formulations including one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the protein or checkpoint kinases using such compounds or pharmaceutical compositions.

This application claims the benefit of priority from U.S. ProvisionalPatent Application Ser. No. 60/811,351, filed on Jun. 6, 2006.

FIELD OF THE INVENTION

The present invention relates to imidazo[1,2-a]pyrazine compounds usefulas protein kinase inhibitors, regulators or modulators, pharmaceuticalcompositions containing the compounds, and methods of treatment usingthe compounds and compositions to treat diseases such as, for example,cancer, inflammation, arthritis, viral diseases, neurodegenerativediseases such as Alzheimer's disease, cardiovascular diseases, andfungal diseases.

BACKGROUND OF THE INVENTION

Protein kinases are a family of enzymes that catalyze phosphorylation ofproteins, in particular the hydroxyl group of specific tyrosine, serine,or threonine residues in proteins. Protein kinases are pivotal in theregulation of a wide variety of cellular processes, includingmetabolism, cell proliferation, cell differentiation, and cell survival.Uncontrolled proliferation is a hallmark of cancer cells, and can bemanifested by a deregulation of the cell division cycle in one of twoways—making stimulatory genes hyperactive or inhibitory genes inactive.Protein kinase inhibitors, regulators or modulators alter the functionof kinases such as cyclin-dependent kinases (CDKs), mitogen activatedprotein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta),Checkpoint (Chk) (e.g., CHK-1, CHK-2 etc.) kinases, AKT kinases, JNK,and the like. Examples of protein kinase inhibitors are described inWO02/22610 A1 and by Y. Mettey et al in J. Med. Chem., (2003) 46222-236.

The cyclin-dependent kinases are serine/threonine protein kinases, whichare the driving force behind the cell cycle and cell proliferation.Misregulation of CDK function occurs with high frequency in manyimportant solid tumors. Individual CDK's, such as, CDK1, CDK2, CDK3,CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles incell cycle progression and can be classified as either G1, S, or G2Mphase enzymes CDK2 and CDK4 are of particular interest because theiractivities are frequently misregulated in a wide variety of humancancers. CDK2 activity is required for progression through G1 to the Sphase of the cell cycle, and CDK2 is one of the key components of the G1checkpoint. Checkpoints serve to maintain the proper sequence of cellcycle events and allow the cell to respond to insults or toproliferative signals, while the loss of proper checkpoint control incancer cells contributes to tumorgenesis. The CDK2 pathway influencestumorgenesis at the level of tumor suppressor function (e.g. p52, RB,and p27) and oncogene activation (cyclin E). Many reports havedemonstrated that both the coactivator, cyclin E, and the inhibitor,p27, of CDK2 are either over- or underexpressed, respectively, inbreast, colon, nonsmall cell lung, gastric, prostate, bladder,non-Hodgkin's lymphoma, ovarian, and other cancers. Their alteredexpression has been shown to correlate with increased CDK2 activitylevels and poor overall survival. This observation makes CDK2 and itsregulatory pathways compelling targets for the development of cancertreatments.

A number of adenosine 5′-triphosphate (ATP) competitive small organicmolecules as well as peptides have been reported in the literature asCDK inhibitors for the potential treatment of cancers. U.S. Pat. No.6,413,974, col. 1, line 23-col. 15, line 10 offers a good description ofthe various CDKs and their relationship to various types of cancer.Flavopiridol (shown below) is a nonselective CDK inhibitor that iscurrently undergoing human clinical trials, A. M. Sanderowicz et al, J.Clin. Oncol. (1998) 16, 2986-2999.

Other known inhibitors of CDKs include, for example, olomoucine (J.Vesely et al, Euro J. Biochem., (1994) 224, 771-786) and roscovitine (I.Meijer et al, Eur. J. Biochem, (1997) 243, 527-536). U.S. Pat. No.6,107,305 describes certain pyrazolo[3,4-b]pyridine compounds as CDKinhibitors. An illustrative compound from the '305 patent is:

K. S. Kim et a, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162disclose certain aminothiazole compounds as CDK inhibitors.

Imidazopyrazines are known. For example, U.S. Pat. No. 6,919,341 (thedisclosure of which is incorporated herein by reference) andUS2005/0009832 disclose various imidazopyrazines. Also being mentionedare the following: WO2005/047290; US2005/095616; WO2005/039393;WO2005/019220; WO2004/072081; WO2005/014599; WO2005/009354;WO2005/005429; WO2005/085252; US2005/009832; US2004/220189;WO2004/074289; WO2004/026877; WO2004/026310; WO2004/022562;WO2003/089434; WO2003/084959; WO2003/051346; US2003/022898;WO2002/060492; WO2002/060386; WO2002/028860; JP (1986)61-057587; J.Burke et at, J. Biological Chem., Vol. 278(3), 1450-1456 (2003); and F.Bondavalli et al, J. Med. Chem., Vol. 45 (22), 4875-4887 (2002).Additionally, commonly owned, U.S. Pat. No. 6,919,341, and pending U.S.provisional patent application Ser. No. 60/735,982 filed Nov. 10, 2005,and incorporated herein by reference, disclose severalimidazo[1,2-a]pyrazines.

Another series of protein kinases are those that play an important roleas a checkpoint in cell cycle progression, Checkpoints prevent cellcycle progression at inappropriate times, such as in response to DNAdamage, and maintain the metabolic balance of cells while the cell isarrested, and in some instances can induce apoptosis (programmed celldeath) when the requirements of the checkpoint have not been met,Checkpoint control can occur in the G1 phase (prior to DNA synthesis)and in G2, prior to entry into mitosis.

One series of checkpoints monitors the integrity of the genome and, uponsensing DNA damage, these “DNA damage checkpoints” block cell cycleprogression in G₁ & G₂ phases, and slow progression through S phase.This action enables DNA repair processes to complete their tasks beforereplication of the genome and subsequent separation of this geneticmaterial into new daughter cells takes place. Inactivation of CHK1 hasbeen shown to transduce signals from the DNA-damage sensory complex toinhibit activation of the cyclin B/Cdc2 kinase, which promotes mitoticentry, and abrogate G.sub.2 arrest induced by DNA damage inflicted byeither anticancer agents or endogenous DNA damage, as well as result inpreferential killing of the resulting checkpoint defective cells. See,e.g., Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al.,Science, 277, 1497-1501 (1997), Nurse, Cell 91, 865-867 (1997); Weinert,Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363, 368-371(1993); and Al-Khodairy et al., Molec. Biol. Cell., 5, 147-160 (1994).

Selective manipulation of checkpoint control in cancer cells couldafford broad utilization in cancer chemotherapeutic and radiotherapyregimens and may, in addition, offer a common hallmark of human cancer“genomic instability” to be exploited as the selective basis for thedestruction of cancer cells. A number of factors place CHK1 as a pivotaltarget in DNA-damage checkpoint control. The elucidation of inhibitorsof this and functionally related kinases such as CDS1/CHK2, a kinaserecently discovered to cooperate with CHK1 in regulating S phaseprogression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka,Science, 282, 1893-1897 (1998)), could provide valuable new therapeuticentities for the treatment of cancer.

Another group of kinases are the tyrosine kinases. Tyrosine kinases canbe of the receptor type (having extracellular, transmembrane andintracellular domains) or the non-receptor type (being whollyintracellular). Receptor-type tyrosine kinases are comprised of a largenumber of transmembrane receptors with diverse biological activity. Infact, about 20 different subfamilies of receptor-type tyrosine kinaseshave been identified. One tyrosine kinase subfamily, designated the HERsubfamily, is comprised of EGFR (HER1), HER2, HER3 and HER4. Ligands ofthis subfamily of receptors identified so far include epithelial growthfactor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.Another subfamily of these receptor-type tyrosine kinases is the insulinsubfamily, which includes INS-R, IGF-IR, IR, and IR-R. The PDGFsubfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit andFLK-II. The FLK family is comprised of the kinase insert domain receptor(KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) andthe fms-like tyrosine kinase-1 (flt-1). For detailed discussion of thereceptor-type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339,1994.

At least one of the non-receptor protein tyrosine kinases, namely, LCK,is believed to mediate the transduction in T-cells of a signal from theinteraction of a cell-surface protein (Cd4) with a cross-linked anti-Cd4antibody. A more detailed discussion of non-receptor tyrosine kinases isprovided in Bolen, Oncogene, 8, 2025-2031 (1993). The non-receptor typeof tyrosine kinases is also comprised of numerous subfamilies, includingSrc, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Eachof these subfamilies is further sub-divided into varying receptors. Forexample, the Src subfamily is one of the largest and includes Src, Yes,Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes hasbeen linked to oncogenesis. For a more detailed discussion of thenon-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031(1993).

In addition to its role in cell-cycle control, protein kinases also playa crucial role in angiogenesis, which is the mechanism by which newcapillaries are formed from existing vessels. When required, thevascular system has the potential to generate new capillary networks inorder to maintain the proper functioning of tissues and organs. In theadult, however, angiogenesis is fairly limited, occurring only in theprocess of wound healing and neovascularization of the endometriumduring menstruation. On the other hand, unwanted angiogenesis is ahallmark of several diseases, such as retinopathies, psoriasis,rheumatoid arthritis, age-related macular degeneration, and cancer(solid tumors). Protein kinases which have been shown to be involved inthe angiogenic process include three members of the growth factorreceptor tyrosine kinase family; VEGF-R2 (vascular endothelial growthfactor receptor 2, also known as KDR (kinase insert domain receptor) andas FLK 1); FGF-R (fibroblast growth factor receptor); and TEK (alsoknown as Tie-2).

VEGF-R2, which is expressed only on endothelial cells, binds the potentangiogenic growth factor VEGF and mediates the subsequent signaltransduction through activation of its intracellular kinase activity.Thus, it is expected that direct inhibition of the kinase activity ofVEGF-R2 will result in the reduction of angiogenesis even in thepresence of exogenous VEGF (see Strawn et al, Cancer Research, 56,3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which failto mediate signal transduction. Millauer et al, Cancer Research, 56,1615-1620 (1996). Furthermore, VEGF-R2 appears to have no function inthe adult beyond that of mediating the angiogenic activity of VEGF.Therefore, a selective inhibitor of the kinase activity of VEGF-R2 wouldbe expected to exhibit little toxicity.

Similarly, FGFR binds the angiogenic growth factors aFGF and bFGF andmediates subsequent intracellular signal transduction. Recently, it hasbeen suggested that growth factors such as bFGF may play a critical rolein inducing angiogenesis in solid tumors that have reached a certainsize. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). UnlikeVEGF-R2, however, FGF-R is expressed in a number of different cell typesthroughout the body and may or may not play important roles in othernormal physiological processes in the adult. Nonetheless, systemicadministration of a small molecule inhibitor of the kinase activity ofFGF-R has been reported to block bFGF-induced angiogenesis in micewithout apparent toxicity. Mohammad et al., EMBO Journal 17, 5996-5904(1998).

TEK (also known as Tie-2) is another receptor tyrosine kinase expressedonly on endothelial cells which has been shown to play a role inangiogenesis. The binding of the factor angiopoietin-1 results inautophosphorylation of the kinase domain of TEK and results in a signaltransduction process which appears to mediate the interaction ofendothelial cells with peri-endothelial support cells, therebyfacilitating the maturation of newly formed blood vessels. The factorangiopoietin-2, on the other hand, appears to antagonize the action ofangiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al.,Science, 277, 55-60 (1997).

The kinase, JNK, belongs to the mitogen-activated protein kinase (MAPK)superfamily, JNK plays a crucial role in inflammatory responses, stressresponses, cell proliferation, apoptosis, and tumorigenesis. JNK kinaseactivity can be activated by various stimuli, including theproinflammatory cytokines (TNF-alpha and interleukin-1), lymphocytecostimulatory receptors (CD28 and CD40), DNA-damaging chemicals,radiation, and Fas signaling. Results from the JNK knockout miceindicate that JNK is involved in apoptosis induction and T helper celldifferentiation.

Pim-1 is a small serine/threonine kinase. Elevated expression levels ofPim-1 have been detected in lymphoid and myeloid malignancies, andrecently Pim-1 was identified as a prognostic marker in prostate cancer.K. Peltola, “Signaling in Cancer: Pim-1 Kinase and its Partners”,Annales Universitatis Turkuensis, Sarja-Ser. D Osa-Tom. 616, (Aug. 30,2005), http://kirjasto.utu.fi/julkaisupalvelut/annaalit/2004/D616.html.Pim-1 acts as a cell survival factor and may prevent apoptosis inmalignant cells. K. Petersen Shay et al., Molecular Cancer Research3:170-181 (2005).

There is a need for effective inhibitors of protein kinases in order totreat or prevent disease states associated with abnormal cellproliferation, Moreover, it is desirable for kinase inhibitors topossess both high affinity for the target kinase as well as highselectivity versus other protein kinases. Small-molecule compounds thatmay be readily synthesized and are potent inhibitors of cellproliferation are those, for example, that are inhibitors of one or moreprotein kinases, such as CHK1, CHK2, VEGF (VEGF-R2), Pim-1, CDKs orCDK/cyclin complexes and both receptor and non-receptor tyrosinekinases.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofimidazo[1,2-a]pyrazine compounds, methods of preparing such compounds,pharmaceutical compositions comprising one or more such compounds,methods of preparing pharmaceutical formulations comprising one or moresuch compounds, and methods of treatment, prevention, inhibition oramelioration of one or more diseases associated with protein kinasesusing such compounds or pharmaceutical compositions.

In one aspect, the present invention provides compounds represented byFormula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof, wherein:

-   R is selected from the group consisting of H, halo, amino, alkyl,    aryl, heteroaryl, heteroarylalkyl-, cycloalkyl, cycloalkylalkyl-,    cycloalkenyl, cycloalkenylalkyl-, arylalkyl-, heterocyclyl,    heterocyclylalkyl-, heterocyclenyl, heterocyclenylalkyl-, alkenyl-,    alkynyl-, and —CN, wherein each of said alkyl, aryl, heteroaryl,    heterocyclyl and cycloalkyl can be unsubstituted or optionally    independently substituted with one or more moieties which can be the    same or different each moiety being independently selected from    halo, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵;-   R¹ is selected from the group consisting of H, alkyl, aryl,    arylalkyl-, heteroaryl, heteroarylalkyl-, cycloalkenyl,    cycloalkenylalkyl, arylalkyl-, heterocyclyl, heterocyclylalkyl-,    heterocyclenyl, heterocyclenylalkyl, and —C(O)—N(R¹⁴R¹⁵), wherein    each of said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl    can be unsubstituted or optionally independently substituted with    one or more moieties which can be the same or different each moiety    being independently selected from halo, alkyl, aryl, cyano, —OR¹⁴,    —SR¹⁴, —S(O)R¹⁴, —S(O₂)R¹⁴, —N(R¹⁴R¹⁵), —C(O)O-alkyl,    —C(O)—N(R¹⁴R¹⁵), —N(R¹⁴)S(O₂)R¹⁵, and —N(R¹⁴)C(O)R¹⁵;-   R² is selected from the group consisting of H, halo, amino, alkyl,    aryl, heteroaryl, heteroarylalkyl-, cycloalkyl, cycloalkylalkyl-,    cycloalkenyl, cycloalkenylalkyl, arylalkyl-, heterocyclyl,    heterocyclylalkyl-, heterocyclenyl, heterocyclenylalkyl, alkenyl,    alkynyl, and —CN, wherein each of said alkyl, aryl, heteroaryl,    heterocyclyl and cycloalkyl can be unsubstituted or optionally    independently substituted with one or more moieties which can be the    same or different each moiety being independently selected from    halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵;-   R³ is selected from the group consisting of H, alkyl, amino, aryl,    heteroaryl, heteroarylalkyl-, cycloalkyl, cycloalkylalkyl-,    cycloalkenyl, cycloalkenylalkyl, arylalkyl-, heterocyclyl,    heterocyclylalkyl-, heterocyclenyl, heterocyclenylalkyl, alkenyl,    alkynyl, —C(O)—N(R¹⁴R¹⁵ and —CN, wherein each of said alkyl, aryl,    heteroaryl, heterocyclyl and cycloalkyl can be unsubstituted or    optionally independently substituted with one or more moieties which    can be the same or different each moiety being independently    selected from halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and    —N(R¹⁴)C(O)R¹⁵;-   X is selected from the group consisting of a covalent bond,    —C(O)—NR¹⁴, —S(O₂)N(R¹⁴)—, —N(R¹⁴)—C(O)—N(R¹⁵), —C(O)—O—, —O—C(O)—,    —O—C(O)—N(R¹⁴)—, —N(R¹⁴)—, —C(R¹⁴R¹⁵)—, —O—, —S—, —S(O)—, and    —S(O₂)—; or the moiety-    where n1 is 1-3;-   R⁴ is selected from the group consisting of alkyl, —C(O)O-alkyl,    heterocyclyl, aryl, and amino, wherein each of said alkyl, aryl and    heterocyclyl can be unsubstituted or optionally independently    substituted with one or more moieties which can be the same or    different each moiety being independently selected from halo, alkyl,    cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵),    —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(O)O-alkyl,    —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and    —N(R¹⁴)—CO—N(R¹⁴R¹⁵);-   R⁶ is H, alkyl, cycloalkyl or aryl, wherein each of said alkyl, aryl    and cycloalkyl can be unsubstituted or optionally independently    substituted with one or more moieties which can be the same or    different, each moiety being independently selected from halo,    alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃,    —CF₃, dialkylamino-, alkylthio-, alkylsulfonyl-,    dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl,    —C(O)O-aryl, and —C(O)O-heteroaryl;-   R⁷ is H, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryl    and cycloalkyl can be unsubstituted or optionally independently    substituted with one or more moieties which can be the same or    different, each moiety being independently selected from halo,    alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃,    —CF₃, dialkylamino-, alkylthio-, alkylsulfonyl-,    dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl,    —C(O)O-aryl, and —C(O)O-heteroaryl; and-   R¹⁴ and R¹⁵ can be the same or different, each being independently    selected from the group consisting of H, alkyl, aryl, heteroaryl,    arylalkyl, cycloalkyl, heterocyclyl, acyl, halo, hydroxyalkyl,    trifluoromethyl, —OR⁶, —OCF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN,    —S(O₂)N(R⁶R⁷) and —NO₂, wherein each of said alkyl, aryl,    heteroaryl, cycloalkyl and heterocyclyl can be unsubstituted or    optionally independently substituted with one or more moieties which    can be the same or different each moiety being independently    selected from halo, alkyl, cyano, acyl, hydroxyalkyl,    trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,    —S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and    —C(O)O-heteroaryl;    with the proviso that the invention excludes the following    compounds:

When X is a covalent bond, R⁴ is directly bonded to the imidazole ring.

The compounds of Formula I can be useful as protein kinase inhibitorsand can be useful in the treatment and prevention of proliferativediseases, for example, cancer, inflammation and arthritis,neurodegenerative diseases such Alzheimer's disease, cardiovasculardiseases, viral diseases and fungal diseases.

DETAILED DESCRIPTION

In an embodiment, the present invention provides imidazopyrazinecompounds, especially imidazo[1,2-a]pyrazine compounds which arerepresented by structural Formula I, or pharmaceutically acceptablesalts, solvates, esters or prodrug thereof, wherein the various moietiesare as described above.

In another embodiment, in Formula I, R is H, alkyl, aryl, heteroaryl oramino.

In another embodiment, in Formula I, R is H.

In another embodiment, in Formula I, R¹ is selected from H,unsubstituted aryl, aryl substituted with one or more moieties selectedfrom the group consisting of halo, alkyl, cyano, alkoxy, aryl,alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) andN(R¹⁴)C(O)R¹⁵, unsubstituted heteroaryl and heteroaryl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula II, R¹ is H.

In another embodiment, in Formula I, R¹ is unsubstituted aryl.

In another embodiment, in Formula II, R¹ is aryl substituted with one ormore moieties selected from the group consisting of halo, alkyl, cyano,alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R¹ is aryl substituted with one ormore moieties selected from the group consisting of halo, alkyl, alkoxy,aryl, —CF₃, —OCF₃,

In another embodiment, in Formula I, R¹ is unsubstituted heteroaryl.

In another embodiment, in Formula I, R¹ is heteroaryl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R¹ is a pyrazolyl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R¹ is a thiophenyl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R¹ is a benzothiophenyl substitutedwith one or more moieties selected from the group consisting of halo,alkyl, cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃,—N(R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R¹ is a pyrazolyl substituted withone or more moieties selected from the group consisting of methyl,cyano, phenyl, 4-chlorophenyl, —CO₂Et, —CO₂H and —C(O)NMe₂.

In another embodiment, in Formula I, R¹ is a thiophenyl substituted withone or more moieties selected from the group consisting of methyl,cyano, phenyl, 4-chlorophenyl, —CO₂Et, —CO₂H and —C(O)NMe₂.

In another embodiment, in Formula I, R¹ is a benzothiophenyl substitutedwith one or more moieties selected from the group consisting of methyl,cyano, phenyl, 4-chlorophenyl, —CO₂Et, —CO₂H and —C(O)NMe₂.

In another embodiment, in Formula I, R¹ is pyrazolyl substituted withalkyl.

In another embodiment, in Formula I, R¹ is 1-methyl-pyrazol-4-yl.

In another embodiment, in Formula I, R² is H, unsubstituted aryl, arylsubstituted with one or more moieties selected from the group consistingof halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵,unsubstituted heteroaryl and heteroaryl substituted with one or moremoieties selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R² is H.

In another embodiment, in Formula I, R² is unsubstituted aryl.

In another embodiment, in Formula I, R² is aryl substituted with one ormore moieties selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R² is unsubstituted heteroaryl.

In another embodiment, in Formula I, R² is heteroaryl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R² is selected from the groupconsisting of

where R¹⁴ is as discussed above, n is 0-3 and R¹⁶ is selected from thegroup consisting of alkyl, aryl, cycloalkyl and heteroaryl.

In another embodiment, in Formula I, R² is pyrazolyl.

In another embodiment, in Formula I, R² is pyrazolyl substituted withalkyl.

In another embodiment, in Formula I, R² is 1-methyl-pyrazol-4-yl.

In another embodiment, in Formula I, R³ is selected from H,unsubstituted aryl, aryl substituted with one or more moieties selectedfrom the group consisting of halo, alkyl, cyano, alkoxy, aryl,alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵, unsubstituted heteroaryl and heteroaryl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R³ is H.

In another embodiment, in Formula I, R³ is unsubstituted aryl.

In another embodiment, in Formula I, R³ is aryl substituted with one ormore moieties selected from the group consisting of halo, alkyl, cyano,alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃₁—OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R³ is aryl substituted with one ormore moieties selected from the group consisting of methoxy andcarbethoxy.

In another embodiment, in Formula I, R³ is unsubstituted heteroaryl.

In another embodiment, in Formula I, R³ is heteroaryl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.

In another embodiment, in Formula I, R³ is pyrazolyl.

In another embodiment, in Formula I, R³ is pyrazolyl substituted withalkyl.

In another embodiment, in Formula I, R³ is 1-methyl-pyrazol-4-yl.

In another embodiment of Formula I, R³ is heterocyclyl.

In another embodiment of Formula I, R³ is pieridinyl.

In another embodiment, in Formula I, X is selected from the groupconsisting of a covalent bond, —C(O)—NR¹⁴, —S(O₂)N(R¹⁴)—, —C(O)—O—, and—C(R¹⁴R¹⁵)—.

In another embodiment, in Formula I, R³ is selected from the groupconsisting of:

wherein R¹⁴, n and R¹⁶ are as described earlier.

In another embodiment, in Formula I, X is a covalent bond.

In another embodiment, in Formula I,

In another embodiment, in Formula I,

-X—R⁴ is:

In another embodiment, in Formula I, R⁴ is selected from the groupconsisting of alkyl, —C(O)O-alkyl, heterocyclyl, and aryl, wherein eachof said alkyl, aryl and heterocyclyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different each moiety being independently selected from halo,alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —OR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, in Formula I, R⁴ is selected from the groupconsisting of pyrrolidinyl, piperidinyl, phenyl and ethoxycarbonyl,wherein each of said pyrrolidinyl, piperidinyl and phenyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R^(‥), —C(O)O-alkyl,—OR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵), In another embodiment,in Formula I, R⁴ is selected from the group consisting of: alkyl,

wherein R⁸ is selected from the group consisting of H, NH₂, N(R¹⁴R¹⁵)and (R¹⁴R¹⁵)N—N(R¹⁴R¹⁵);

n is 0-2; and

R⁹, R¹⁰, R¹¹ and R¹² can be the same or different, each beingindependently selected from the group consisting of H, alkyl,cycloalkyl, heterocyclyl, aryl and heteroaryl.

In another embodiment, in Formula I, R⁴ is pyrrolidinyl wherein saidpyrrolidinyl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵,—C(O)O-alkyl, —OR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, in Formula I, R⁴ is piperidinyl wherein saidpiperidinyl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —OR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, in Formula I, R⁴ is phenyl wherein said phenylcan be unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —OR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵)

In another embodiment, in Formula I, R⁴ is ethoxycarbonyl)

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is heteroaryl, R═R¹═H, X is a covalent bond, R³ and R⁴ are bothunsubstituted aryl, wherein each of said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above.

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═R¹═H, X is a covalent bond, R³ and R⁴ are bothunsubstituted pyrazolyl, wherein said pyrazolyl can be unsubstituted orsubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from the group consisting ofhalo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵,wherein R¹⁴ and R¹⁵ are as defined above.

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is heteroaryl, R═R¹═H, X is a covalent bond, R³ and R⁴ are both aryl,wherein said each of aryl and heteroaryl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different each moiety being independently selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵)and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ are as defined above.

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═R¹═H, X is a covalent bond, R³ and R⁴ are botharyl, wherein each of said pyrazolyl and aryl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different each moiety being independently selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵)and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ are as defined above.

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═R¹═H, X is a covalent bond, R³ is aryl and R⁴ is aheterocyclyl, wherein each of said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR⁴, —SR¹⁴—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═R¹═H, X is a covalent bond, R³ is aryl and R⁴ is aheterocyclyl, wherein each of said pyrazolyl and aryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═R¹═H, X is a covalent bond, R³ is heteroaryl and R⁴is a heterocyclyl, wherein each of said pyrazolyl and heteroaryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴—O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═H, R1 is aryl, X is a covalent bond, R³ is aryland R⁴ is a heterocyclyl, wherein each of said aryl and heteroaryl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴—O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═H, R¹ is heteroaryl, X is a covalent bond, R³ isaryl and R⁴ is a heterocyclyl, wherein each of said aryl and heteroarylcan be unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═H, R¹ is heteroaryl, X is a covalent bond, R³ isheteroaryl and R⁴ is a heterocyclyl, wherein each of said heteroarylscan be unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, C(O)O-aryl,C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═H, R¹ is aryl, X is a covalent bond, R³ is aryl andR⁴ is a heterocyclyl, wherein each of said pyrazolyl and aryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ areas defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═H, R¹ is heteroaryl, X is a covalent bond, R³ isheteroaryl and R⁴ is a heterocyclyl, wherein each of said pyrazolyl andheteroaryl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ andR¹⁵ are as defined above and said heterocyclyl can be unsubstituted oroptionally substituted one or more independently selected R⁸ groups,wherein R⁸ is selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is 1-methyl-pyrazol-4-yl, R═H, R¹ is a heteroaryl, X is a covalentbond, R³ is heteroaryl and R⁴ is a heterocyclyl, wherein each of saidheteroaryls can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ andR¹⁵ are as defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴—O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹═R²=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, R³ is heteroaryland R⁴ is a heterocyclyl, wherein said heteroaryl can be unsubstitutedor substituted with one or more moieties which can be the same ordifferent each moiety being independently selected from the groupconsisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ are as defined above and saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, wherein R⁶ is selected from thegroup consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁶), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹═R²=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, R³ is heteroaryland R⁴ is a heterocyclyl, wherein said heteroaryl can be unsubstitutedor substituted with one or more moieties which can be the same ordifferent each moiety being independently selected from the groupconsisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ and R¹⁵ are as defined above and saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, wherein R⁸ is selected from thegroup consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR1=R²═R³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, and R⁴ is aheterocyclyl, wherein said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl. —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵) and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹═R²═³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, and R⁴ is apiperidinyl, wherein said piperidinyl can be unsubstituted or optionallysubstituted with one or more independently selected R⁸ groups, whereinR⁸ is selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹═R²═R³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, and R⁴ is apyrrolidinyl, wherein said pyrrolidinyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹ is aryl, R²═R³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, andR⁴ is a heterocyclyl, wherein said aryl can be unsubstituted orsubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from the group consisting ofhalo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵,wherein R¹⁴ and R¹⁵ are as defined above and said heterocyclyl can beunsubstituted or optionally substituted with one or more independentlyselected R⁸ groups, wherein R⁸ is selected from the group consisting ofhalo, alkyl, cyano, —N(R¹⁴R¹⁵), —O(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵),—S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl,—C(O)O-aryl, —C(O)O-heteroaryl, —OR⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹ is aryl, R²═R³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, andR⁴ is aryl, wherein said aryl of R¹ can be unsubstituted or substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ andR¹⁵ are as defined above and said aryl of R⁴ may be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵, —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴—SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹ is aryl, R²═R³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, andR⁴ is —C(O)OEt, wherein said aryl can be unsubstituted or substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ andR¹⁵ are as defined above and.

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹ is aryl, R²═R³=1-methyl-pyrazol-4-yl, R═H, X is —C(R¹⁴R¹⁵)—, and R⁴is heterocyclyl, wherein said aryl can be unsubstituted or substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ andR¹⁵ are as defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁶),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).

In another embodiment, this invention discloses a compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is halo or heteroaryl, R═H, R¹=—C(O)—N(R¹⁴R¹⁵), X is a covalent bond,R³ is heterocyclyl and R⁴ is aryl, wherein each of said aryl andheteroaryl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein R¹⁴ andR¹⁵ are as defined above and said heterocyclyl can be unsubstituted oroptionally substituted with one or more halo, alkyl or cyano groups.

In another embodiment, non-limiting examples of compounds of Formula Iinclude:

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.Lower alkyl refers to a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. Lower alkenyl refers toabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl,“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain, Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. Lower alkynyl refers toabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core, Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine, Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein, The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso mean a single moiety (e.g., carbonyl) which simultaneously replacestwo available hydrogens on the same carbon atom on a ring system.Example of such moiety is pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system,Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms,The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described, Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described The bond to the parentmoiety is through the carbonyl, Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl The bond to the parent moiety isthrough the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g., a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS Pharm Sci Tech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or FR configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵ N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays, Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula I can be inhibitors,regulators or modulators of protein kinases. Non-limiting examples ofprotein kinases that can be inhibited, regulated or modulated includecyclin-dependent kinases (CDKs), such as, CDK1, CDK2, CDK3, CDK4, CDK5,CDK6 and CDK7, CDK8, mitogen activated protein kinase (MAPK/ERK),glycogen synthase kinase 3 (GSK3beta), Pim-1 kinases, Chk kinases, suchas Chk1 and Chk2, tyrosine kinases, such as the HER subfamily(including, for example, EGFR (HER1), HER2, HER3 and HER4), the insulinsubfamily (including, for example, INS-R, IGF-IR, IR, and IR-R), thePDGF subfamily (including, for example, PDGF-alpha and beta receptors,CSFIR, c-kit and FLK-II), the FLK family (including, for example, kinaseinsert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liverkinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1)),non-receptor protein tyrosine kinases, for example LGK, Src, Frk, Btk,Csk, Abl Zap70, Fes/Fps, Fak, Jak, Ack, and LMK, growth factor receptortyrosine kinases such as VEGF-R2, FGF-R, TEK, Akt kinases and the like.

The compounds of Formula (I) can be inhibitors of protein kinases suchas, for example, the inhibitors of the checkpoint kinases such as Chk1,Chk2 and the like. Preferred compounds can exhibit IC₅₀ values of lessthan about 5 μm, preferably about 0.001 to about 1.0 μm, and morepreferably about 0.001 to about 0.1 μm. The assay methods are describedin the Examples set forth below.

The compounds of Formula I can be useful in the therapy of proliferativediseases such as cancer, autoimmune diseases, viral diseases, fungaldiseases, neurological/neurodegenerative disorders, arthritis,inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal,alopecia and cardiovascular disease. Many of these diseases anddisorders are listed in U.S. Pat. No. 6,413,974 cited earlier,incorporated by reference herein.

More specifically, the compounds of Formula I can be useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing: carcinoma, including that of the bladder, breast, colon,kidney, liver, lung, including small cell lung cancer, non-small celllung cancer, head and neck, esophagus, gall bladder, ovary, pancreas,stomach, cervix, thyroid, prostate, and skin, including squamous cellcarcinoma;

hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma,non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma,myeloma, and Burkett's lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; and

other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma.

Due to the key role of CDKs in the regulation of cellular proliferationin general, inhibitors could act as reversible cytostatic agents whichmay be useful in the treatment of any disease process which featuresabnormal cellular proliferation, e.g., benign prostate hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosisfollowing angioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

Compounds of Formula I may also be useful in the treatment ofAlzheimer's disease, as suggested by the recent finding that CDK5 isinvolved in the phosphorylation of tau protein (J. Biochem, (1995) 117,741-749).

Compounds of Formula I may induce or inhibit apoptosis. The apoptoticresponse is aberrant in a variety of human diseases. Compounds ofFormula I, as modulators of apoptosis, will be useful in the treatmentof cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited to herpevirus,poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), preventionof AIDS development in HIV-infected individuals, autoimmune diseases(including but not limited to systemic lupus, erythematosus, autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus),neurodegenerative disorders (including but not limited to Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration), myelodysplastic syndromes, aplastic anemia, ischemicinjury associated with myocardial infarctions, stroke and reperfusioninjury, arrhythmia, atherosclerosis, toxin-induced or alcohol relatedliver diseases, hematological diseases (including but not limited tochronic anemia and aplastic anemia), degenerative diseases of themusculoskeletal system (including but not limited to osteoporosis andarthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

Compounds of Formula I, as inhibitors of the CDKs, can modulate thelevel of cellular RNA and DNA synthesis. These agents would therefore beuseful in the treatment of viral infections (including but not limitedto HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barrvirus, Sindbis virus and adenovirus).

Compounds of Formula I may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of Formula I may also be useful in inhibiting tumorangiogenesis and metastasis.

Compounds of Formula I may also act as inhibitors of other proteinkinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP kinase, EGFreceptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abland thus be effective in the treatment of diseases associated with otherprotein kinases.

Another aspect of this invention is a method of treating a mammal (e.g.,human) having a disease or condition associated with the CDKs byadministering a therapeutically effective amount of at least onecompound of Formula I, or a pharmaceutically acceptable salt, solvate,ester or prodrug of said compound to the mammal.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of Formula I. An especially preferred dosage is about 0.01 to25 mg/kg of body weight/day of a compound of Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound.

The compounds of this invention may also be useful in combination(administered together, concurrently, as fixed dose, or sequentially)with one or more of anti-cancer treatments such as radiation therapy,and/or one or more anti-cancer agents different from the compound ofFormula I. The compounds of the present invention can be present in thesame dosage unit as the anti-cancer agent or in separate dosage units.

Another aspect of the present invention is a method of treating one ormore diseases associated with cyclin dependent kinase, comprisingadministering to a mammal in need of such treatment an amount of a firstcompound, which is a compound of Formula I, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof; and an amount of atleast one second compound, the second compound being an anti-canceragent different from the compound of Formula I, wherein the amounts ofthe first compound and the second compound result in a therapeuticeffect.

Non-limiting examples of suitable anti-cancer agents include cytostaticagents, cytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil); anti-metabolites (such asmethoxtrexate); alkylating agents (such as temozolomide (TEMODAR™ fromSchering-Plough Corporation, Kenilworth, N.J.), cyclophosphamide);Farnesyl protein transferase inhibitors (such as, SARASAR™(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide,or SCH 66336 from Schering-Plough Corporation, Kenilworth, N.J.),tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals), L778123(a farnesyl protein transferase inhibitor from Merck & Company,Whitehouse Station, N.J.), BMS 214662 (a farnesyl protein transferaseinhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.);signal transduction inhibitors (such as, Iressa® (or gefitinib fromAstra Zeneca Pharmaceuticals, England), Tarceva® (ertotinibhydrochloride) (EGFR kinase inhibitors), antibodies to EGFR (e.g.,C225), GLEEVEC® (imatinib, a C-abl kinase inhibitor from NovartisPharmaceuticals, East Hanover, N.J.); interferons such as, for example,intron (from Schering-Plough Corporation), Peg-Intron (fromSchering-Plough Corporation), hormonal therapy combinations; aromatasecombinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine, Busulfan, Carmustine,Lomustine, triethylenethiophosphoramine, Streptozocin, Dacarbazine,Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabinephosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN™ fromSanofi-Synthelabo Pharmaceuticals, France), Pentostatine, Vinblastine,Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin,Mitomycin-C, L-Asparaginase, Teniposide 170α-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Dromostanolone propionate, Testolactone, Megestrolacetate,Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone,Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine,Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole,Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin,Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine,Profimer, Erbitux® (cetuximab from Bristol-Myers Squibb), Liposomal,Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant,Exemestane, Ifosfomide, Rituximab, C225 (from Merck KGaA, Darmstadt,Germany), Doxil (from Johnson & Johnson, New Brunswick, N.J.), Ontak(from Seragen), Depocyt (from SkyePharma), Mylotarg (from WyethPharmaceuticals), Campath (from Genzyme/Ilex Technology), Celebrex (fromPfizer, New York, N.Y.), Sutent (from Pfizer), Aranesp (from Amgen),Neupogen (from Amgen), Neulasta (from Amgen), Kepivance (from Amgen),SU11248 and PTK787.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. For example, the CDC2 inhibitor olomucine has been found to actsynergistically with known cytotoxic agents in inducing apoptosis (JCell Sci, (1995) 108, 2897. Compounds of Formula I may also beadministered sequentially with known anticancer or cytotoxic agents whena combination formulation is inappropriate. The invention is not limitedin the sequence of administration; compounds of Formula I may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research,(1997) 57, 3375. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof, andan amount of one or more anti-cancer treatments and anti-cancer agentslisted above wherein the amounts of the compounds/treatments result indesired therapeutic effect.

A method of inhibiting one or more Checkpoint kinases in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of at least one compound of claim 1 or apharmaceutically acceptable salt, solvate, ester or prodrug thereof.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or moreCheckpoint kinases in a patient in need thereof, comprisingadministering a therapeutically effective amount of at least onecompound of claim 1 or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof.

Yet another aspect of the present invention is a method of treating oneor more diseases associated with Checkpoint kinase, comprisingadministering to a mammal in need of such treatment an amount of a firstcompound, which is a compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof; and an amount of atleast one second compound, the second compound being an anti-canceragent, wherein the amounts of the first compound and the second compoundresult in a therapeutic effect.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or moreCheckpoint kinases in a patient in need thereof, comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising in combination at least one pharmaceuticallyacceptable carrier and at least one compound according to claim 1, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof.

In the above methods, the checkpoint kinase to be inhibited can be Chk1and/or Chk2.

Another aspect of the present invention is a method of inhibiting one ormore tyrosine kinases in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of atleast one compound of Formula 1 or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof.

Yet another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or moretyrosine kinases in a patient in need thereof, comprising administeringa therapeutically effective amount of at least one compound of Formula 1or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof.

Another aspect of the present invention is a method of treating one ormore diseases associated with tyrosine kinase, comprising administeringto a mammal in need of such treatment an amount of a first compound,which is a compound of Formula 1, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof; and an amount of at least one secondcompound, the second compound being an anti-cancer agent, wherein theamounts of the first compound and the second compound result in atherapeutic effect.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or moretyrosine kinases in a patient in need thereof, comprising administeringa therapeutically effective amount of a pharmaceutical compositioncomprising in combination at least one pharmaceutically acceptablecarrier and at least one compound according to Formula 1 or apharmaceutically acceptable salt, solvate, ester or prodrug thereof.

In the above methods, the tyrosine kinase can be VEGFR (VEGF-R2), EGFR,HER2, SRC, JAK and/or TEK.

Another aspect of the present invention is a method of inhibiting one ormore Pim-1 kinases in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of atleast one compound of Formula 1 or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof.

Yet another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or more Pim-1kinases in a patient in need thereof, comprising administering atherapeutically effective amount of at least one compound of Formula Ior a pharmaceutically acceptable salt, solvate, ester or prodrugthereof.

Another aspect of the present invention is a method of treating one ormore diseases associated with Pim-1 kinase, comprising administering toa mammal in need of such treatment an amount of a first compound, whichis a compound of Formula 1, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof; and an amount of at least one secondcompound, the second compound being an anti-cancer agent, wherein theamounts of the first compound and the second compound result in atherapeutic effect.

Another aspect of the present invention is a method of treating, orslowing the progression of, a disease associated with one or more Pim-1kinases in a patient in need thereof, comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising in combination at least one pharmaceutically acceptablecarrier and at least one compound according to Formula 1 or apharmaceutically acceptable salt, solvate, ester or prodrug thereof.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described herein below have beencarried out with compounds according to the invention and their salts,solvates, esters or prodrugs.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula I, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug of said compound and at leastone pharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally or intravenously orintrathecally or some suitable combination(s) thereof.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound and a pharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula I, or a pharmaceutically acceptable salt,solvate, ester or prodrug of said compound and an amount of at least oneanticancer therapy and/or anticancer agent listed above, wherein theamounts of the two or more ingredients result in desired therapeuticeffect.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on a VarianAS-400 (400 MHz) and are reported as ppm down field from Me₄Si withnumber of protons, multiplicities, and coupling constants in Hertzindicated parenthetically. Where LC/MS data are presented, analyses wasperformed using an Applied Biosystems API-100 mass spectrometer andShimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mmID; gradient flow: 0 min—10% CH₃CN, 5 min—95% CH₃CN, 7 min—95% CH₃CN,7.5 min—10% CH₃CN, 9 min—stop. The retention time and observed parention are given.

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

-   Thin layer chromatography: TLC-   dichloromethane: CH₂Cl₂-   ethyl acetate: AcOEt or EtOAc-   methanol: MeOH-   trifluoroacetate: TFA-   triethylamine: Et₃N or TEA-   butoxycarbonyl: n-Boc or Boc-   nuclear magnetic resonance spectroscopy: NMR-   liquid chromatography mass spectrometry: LCMS-   high resolution mass spectrometry: HRMS-   milliliters: mL-   millimoles: mmol-   microliters: μl-   grams: g-   milligrams: mg-   room temperature or rt (ambient): about 25° C.-   dimethoxyethane; DME

The synthesis of the inventive compounds is illustrated below. Also, itshould be noted that the disclosure of commonly-owned U.S. Pat. No.6,919,341 is incorporated herein by reference.

Synthesis

A general scheme to synthesize the compounds of the invention is shownbelow:

Specific, non-limiting, synthetic procedures are described below:

EXAMPLE 1

Part A:

The 2-amino-3-chloropyrazine 1 (129 mg, 1.0 mmol) was dissolved in DMF(1 mL) and EtOH (1 mL). NaSMe (105 mg, 1.5 mmol) was added carefully andthe resulting mixture was heated up to 80° C. and stirred for 3 hours.After cooling to room temperature and concentration, the residue wasdiluted with H₂O and extracted with DCM/i-PrOH (9:1). The organics weredried over Na₂SO₄ and concentrated. The resulting residue was purifiedwith column (silica gel, DCM/MeOH=95/5) gave the product 2 (121 mg) assolid. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.73 (d, 1H), 4.66 (s,2H), 2.56 (s, 3H). HPLC-MS t_(R)=0.77 min (UV_(254 nm)); mass calculatedfor formula C₅H₇N₃S 141.0, observed LCMS m/z 142.2 (M+H).

Part B:

n-BuLi (17 ml, 2.5 N in hexane, 44.5 mmol) was added in i-Pr₂NH (6.8 mL,48.6 mmol) in dry THF (20 mL) slowly at −78° C. After completion ofaddition, the mixture was stirred at −78° C. for 30 min, and then it wasallowed to warm to 0° C. The above LDA was added dropwise into asolution of methyl ester (3, ˜10 mmol) and CH₃I (3.2 mL, 44.7 mmol) inTHF (30 mL) at −78° C. through cannula. Addition was completed within 1hour then the mixture was stirred at −78° C. for 1 hour. AcOH (5.5 mL)was added dropwise to quench the reaction at −78° C. After addition, thereaction mixture was stirred at −78° C. for 30 min. then warmed to roomtemperature. Filtered through celite, taken with EtOAc, washed withbrine, Na₂HPO₄ (sat. aq.), 5% NaHSO₃ and brine. The organics were driedover Na₂SO₄. After concentration, the residue was purified with column(silica gel, EtOAc/hexane 20/80) gave the product 4 (2.11 g) as oil.HPLC-MS t_(R)=2.10 min (UV_(254 nm)); mass calculated for formulaC₂₁H₃₀BN₃O₄, 261.1, observed LCMS m/z 262.0 (M+H).

Part C:

To the chloro ketone 4 (261 mg, 1.0 mmol) in DME (4 mL), 2-aminopyrazine(2,121 mg, 0.88 mmol) was added and the mixture was heated up to 90° C.and stirred for 2 days. After cooling to room temperature, the solventwas removed by concentration. The resulting residue was taken with EtOAcand washed with NaHCO₃ (sat. aq.). After drying over Na₂SO₄ andconcentration, the residue was purified with column (silica gel,hexane/EtOAc=50/50 to 20/80) gave the product 5 (222 mg) as oil. ¹H NMR(400 MHz, CDCl₃) δ 7.72 (d, 1H), 7.65 (d, 1H), 7.43 (s, 1H), 4.15 (m,1H), 3.90 (m, 1H), 3.20 (m, 1H), 3.02 (m, 2H), 2.65 (s, 3H), 2.18 (m,1H), 1.65 (m, 3H), 1.44 (s, 9H). HPLC-MS t_(R)=1.86 min (UV_(254 nm));mass calculated for formula C₁₇H₂₄N₄O₂S 348.2, observed LCMS m/z 349.3(M+H).

Part D:

The mixture of compound 5 (700 mg, 2.0 mmol) and m-CPBA (1130 mg, 77%,5.0 mmol) in DCM (20 mL) was stirred at room temperature for 30 min anddiluted with EtOAc (100 mL). The organics were washed with NaHCO₃ (sat.aq., 20 ml×2), brine and dried over Na₂SO₄. After concentration, thecrude product 6 was used in the next step directly without furtherpurification HPLC-MS t_(R)=1.53 min (UV_(254 nm)); mass calculated forformula C₁₇H₂₄N₄O₄S 380.2, observed LCMS m/z 381.2 (M+H).

Part E:

The crude compound 6 from part D was dissolved in NH₃/i-PrOH (4 ml, 2N)and NH₃ (37% in H₂O, 8 mL) and sealed in a high pressure tube. The tubewas heated up 80° C. and stirred overnight. After cooling to roomtemperature, the mixture was concentrated and purified with column(silica gel, DCM/MeOH=95/5) gave the product 7 (470 mg) as solid.HPLC-MS t_(R)=1.04 min (UV_(254 nm)); mass calculated for formulaC₁₆H₂₃N₅O₂ 317.2, observed LCMS m/z 318.3 (M+H).

Part F:

To the solution of compound 7 (740 mg, 2.33 mmol) in CHCl₃ (20 mL), NBS(457 mg, 2.56 mmol) was added at 0° C. The mixture was stirred for 30min over ice-water bath and concentrated. The residue was diluted withEtOAc and washed with NaHCO₃ (sat. aq. 30 mL×2), brine and dried overNa₂SO₄. After concentration, the crude product 8 was used in the nextstep directly without further purification. HPLC-MS t_(R)=1.62 min(UV_(254 nm)); mass calculated for formula C₁₆H₂₂BrN₅O₂ 395.1, observedLCMS m/z 396.1 (M+H).

Part G:

To a 25 ml round bottom flask charged with crude compound 8 (360 mg, 0.9mmol), boronic acid (390 mg, 2.0 mmol), and PdCl₂(dppf) (82 mg, 0.1mmol) was added a DME (4 mL) and Na₂CO₃ (1 mL, sat. aq). The mixture wasthoroughly degassed by alternately connected the flask to vacuum andArgon, This resulting mixture was then heated at 80° C. overnight,diluted by EtOAc (40 ml) and washed with brine, After concentration, theresidue was purified with column (silica gel, EtOAc to EtOAc/MeOH=95/5)to give the product 9 (312 mg) as oil. HPLC-MS t_(R)=1.64 min(UV_(254 nm)); mass calculated for formula C25H₃₁N₅O₄ 465.2, observedLCMS m/z 466.3 (M+H).

Part H:

The mixture of compound 9 (120 mg, 0.26 mmol), LiOH (1N, 5 mL) in THF(10 mL) and MeOH (10 mL) was stirred at room temperature overnight.After concentration, the residue was diluted with water (2 mL) and thepH value was adjusted to 6-7 with HCl (1N). The aqueous was extractedwith EtOAc repeatedly. After drying over Na₂SO₄ and concentration, theresidue was dried under vacuum and used in the next step directlywithout any further purification. HPLC-MS t_(R)=1.30 min (UV_(254 nm));mass calculated for formula C₂₃H₂₇N₅O₄ 437.2, observed LCMS m/z 438.3(M+H).

Part I:

The compound 10 (16 mg, 0.037 mmol) was dissolved in DMF (2 mL), DIEA(18 μL, 0.1 mmol) and HATU (38 mg, 0.1 mmol) were added at roomtemperature followed by the addition of dimethylamine (4 mg, 0.1 mmol).The mixture was stirred over night and purified with HPLC gave compound11. HPLC-MS t_(R)=1.38 min (UV_(254 nm)); mass calculated for formulaC₂₅H₃₂N₆O₃ 464.3, observed LCMS m/z 465.2 (M+H).

Part J:

The compound 11 (10 mg) was treated with HCl (4N in dioxane, 4 mL) andstirred at room temperature for 10 min. After concentration, the residuewas dried with lyophilization gave compound 12. HPLC-MS t_(R)=0.61 min(UV_(254 nm)); mass calculated for formula C₂₀H₂₄N₆O 364.2, observedLCMS m/z 365.2 (M+H).

EXAMPLE 2

By essentially the same procedure given in Preparative Example 1, Part Iand part J, compounds (13-17) given in Column 2 of Table 1 can beprepared from compound 10. TABLE 2 MS Exact m/z HPLC Example Structuremass (M + H) MS t_(R) 13

510.2 511.1 1.16 14

470.2 471.3 0.97 15

470.2 471.3 0.97 16

494.2 495.2 1.12 17

460.2 461.2 1.02

EXAMPLE 3

Part A:

The mixture of boronic acid compound 18 (1.66 g, 10 mmol), benzylamine(1.37 g, 10 mmol), DIEA (1.76 mL, 10 mmol) and HATU (3.8 g, 10 mmol) inDMF (20 mL) was stirred at 0° C. overnight After concentration, theresidue was taken up with water (60 mL), the solid was collected withfiltration and washed with water, drying under vacuum gave the product19 as white solid (2.71 g). HPLC-MS t_(R)=1.21 min (UV_(254 nm)); masscalculated for formula C₁₅H₁₆BNO₄ 285.1, observed LCMS m/z 286.1 (M+H).

Part B:

Compound 20 was prepared using the coupling conditions described in partG of Example 1. HPLC-MS t_(R)=1.18 min (UV_(254 nm)); mass calculatedfor formula C₃₁H₃₆N₆O₄ 556.3, observed LCMS m/z 557.3 (M+H).

Part C:

Compound 21 was prepared using the conditions described in part J ofexample 1. HPLC-MS t_(R)=0.92 min (UV_(254 nm)); mass calculated forformula C₁₉H₂₁N₇O 363.2, observed LCMS m/z 364.3 (M+H).

EXAMPLE 4

Part A:

Compound 22 was synthesized using the procedure and condition describedin example 1 part B. HPLC-MS t_(R)=2.03 min (UV_(254 nm)); masscalculated for formula C₁₂H₂₀ClNO₃ 261.1, observed LCMS m/z 262.0 (M+H).

Part B:

Compound 23 was prepared using the cyclization condition described inexample 1 part C. HPLC-MS t_(R)=1.81 min (UV_(254 nm)); mass calculatedfor formula C₁₇H₂₄N₄O₂S 348.2, observed LCMS m/z 349.2 (M+H).

Part C:

Compound 24 was synthesized using the oxidation condition described inexample 1 part D. HPLC-MS t_(R)=1.48 min (UV_(254 nm)); mass calculatedfor formula C₁₇H₂₄N₄O₄S 380.2, observed LCMS m/z 381.2 (M+H),

Part D:

Compound 25 was prepared using the condition described in example 1 partE. HPLC-MS t_(R)=1.04 min (UV_(254 nm)); mass calculated for formulaC₁H₂₃N₅O₂ 317.2, observed LCMS m/z 318.3 (M+H).

Part E:

Compound 26 was synthesized using the condition described in example 1part F. HPLC-MS t_(R)=1.58 min (UV_(254 nm)); mass calculated forformula C₁₆H₂₂BrN₅O₂ 395.1, observed LCMS m/z 396.1 (M+H).

Part F:

Compound 28 was synthesized using the coupling condition described inexample 2 part A. HPLC-MS t_(R)=1.21 min (UV_(254 nm)); mass calculatedfor formula C₁₅H₁₆BNO₄ 285.1, observed LCMS m/z 286.1 (M+H).

Part G:

Compound 29 was prepared using the coupling conditions described inExample 1 part G. HPLC-MS t_(R)=1.51 min (UV_(254 nm)); mass calculatedfor formula C₃₁H₃₆N₆O₄ 556.3, observed LCMS m/z 557.3 (M+H).

Part H:

Compound 30 was synthesized using the deprotection conditions describedin example 1 part J. HPLC-MS t_(R)=0.90 min (UV_(254 nm)); masscalculated for formula C₂₆H₂₈N₆O₂ 456.2, observed LCMS m/z 457.3 (M+H).

EXAMPLE 5

By essentially the same procedure given in Preparative Example 4,compounds 31-43 given in Column 2 of Table 2 can be prepared. TABLE 2 MSExact m/z HPLC Example Structure mass (M + H) MS t_(R) 31

456.2 457.3 0.85 32

442.2 443.2 0.77 33

442.2 443.2 0.81 34

456.2 457.3 0.79 35

297.2 298.3 0.67 36

283.2 284.2 0.61 37

297.2 298.3 0.63 38

313.1 314.1 0.90 39

349.1 350.1 0.87 40

349.1 350.1 1.00 41

313.1 314.1 0.91 42

324.1 325.1 0.80 43

307.2 308.2 0.83

EXAMPLE 6

Part A:

Compound 44 was prepared from compound 25 using the deprotectionconditions described in example 1 part J. HPLC-MS t_(R)=0.61 min(UV_(254 nm)); mass calculated for formula C₁₁H₁₅N₅ 2171, observed LCMSm/z 218.2 (M+H).

EXAMPLE 7

By essentially the same procedure given in Preparative Example 3,compounds given in Column 2 of Table 3 can be prepared. TABLE 3 MS Ex-Exact m/z HPLC ample Structure mass (M + H) MS t_(R) 45

217.1 218.2 0.61 46

203.1 204.2 0.60

EXAMPLE 8

Part A:

To the solution of compound 47 (73 mg, 0.2 mmol) in CHCl₃ (10 mL), NBS(36 mg, 0.2 mmol) was added at room temperature. The mixture was stirredfor 30 min and diluted with EtOAc and washed with NaHCO₃ (sat. aq. 30mL×2), brine and dried over Na₂SO₄. After concentration, the crudeproduct 48 was used in the next step directly without furtherpurification. HPLC-MS t_(R)=1.64 min (UV_(254 nm)); mass calculated forformula C₁₆H₂₁BrN₄O₄S 444.0, observed LCMS m/z 389.0 (M+H-t-Bu).

Part B:

Compound 49 was prepared using the condition described in example 1 partE. HPLC-MS t_(R)=1.31 min (UV_(254 nm)); mass calculated for formulaC₁₅H₂₀BrN₅O₂ 381.1, observed LCMS m/z 382.1 (M+H).

Part C:

Compound 50 was prepared using the coupling condition described inexample 1 part G. HPLC-MS t_(R)=1.12 min (UV_(254 nm)); mass calculatedfor formula C₁₉H₂₅N₇O₂ 383.2, observed LCMS m/z 384.3 (M+H).

Part D:

Compound 51 was prepared using the deprotection condition described inexample 1 part J. HPLC-MS t_(R)=0.62 min (UV_(254 nm)); mass calculatedfor formula C14H₁₇N₇ 283.2, observed LCMS m/z 284.2 (M+H).

EXAMPLE 9

Compound 8 was synthesized in example 1.Part A:

Compound 52 was prepared using the coupling condition described inexample 1 part G. HPLC-MS t_(R)=1.80 min (UV_(254 nm)); mass calculatedfor formula C₂₁H₂₇N₅O₂S 413.2, observed LCMS m/z 414.2 (M+H).

Part B:

The compound 52 (33 mg, 0.08 mmol), 3-iodo-1-methylpyrazole (21 mg, 0.1mmol), K₂CO₃ (27 mg, 0.2 mmol), CuI (2 mg, 0.01 mmol) and trans-N,N′-bismethyl-1,2-cyclohexane diamine (4 μL) were mixed in toluene (3 mL)under Argon. The mixture was sealed under Argon and heated up to 100° C.and stirred overnight. After cooling to room temperature, the reactionwas worked up and the crude was purified by Prep-LC gave the product 53(29 mg). HPLC-MS t_(R)=1.88 min (UV_(254 nm)); mass calculated forformula C₂₅H₃₁N₇O₂S 493.2, observed LCMS m/z 494.2 (M+H).

Part C:

Compound 54 was prepared using the deprotection condition described inexample 1 part J. HPLC-MS t_(R)=1.20 min (UV_(254 nm)); mass calculatedfor formula C₂₀H₂₃N₇S 393.2, observed LCMS m/z 394.1 (M+H).

EXAMPLE 10

Part A:

Compound 55 was prepared starting from compound 7, using the samecoupling condition described in example 9 part B, HPLC-MS t_(R)=1.20 min(UV_(254 nm)); mass calculated for formula C₂₀H₂₃N₇S 393.2, observedLCMS m/z 394.1 (M+H).

Part B:

Compound 56 was prepared using the deprotecting condition described inexample 1 part J. HPLC-MS t_(R)=0.56 min (UV_(254 nm)); mass calculatedfor formula C₁₅H₁₉N₇ 297.2, observed LCMS m/z 298.2 (M+H).

EXAMPLE 11

Compound 52 was synthesized in example 9.Part A:

Compound 52 (˜10 mg) was dissolved in dry THF (5 mL) and1,1,1-trichloroacetyl isocyanate (3 drops) was added and the mixture wasstirred at room temperature for 2 hours. The mixture was concentrated,diluted with MeOH (5 mL) and concentrated again. The crude product wasdried under vacuum for three hours and diluted with MeOH (5 mL). To thismixture, NH₃ (in MeOH, ˜7N, 0.05 mL) was added and the mixture wasstirred for 1 hour at room temperature. After concentration, the crudeproduct 57 was purified by Prep-LC. HPLC-MS t_(R)=1.99 min(UV_(254 nm)); mass calculated for formula C₂₂H₂₈N₆O₃S 456.2, observedLCMS m/z 2457.1 (M+H).

Part B:

Compound 58 was prepared using the deprotection conditions described inexample 1 part J. HPLC-MS t_(R)=1.11 min (UV_(254 nm)); mass calculatedfor formula C₁₇H₂₀N₆OS 356.1, observed LCMS m/z 357.1 (M+H).

EXAMPLE 12

Compound 2 was synthesized in example 1 part A.Part A:

Compound 59 was prepared using the cyclization condition described inexample 1 part C. HPLC-MS t_(R)=1.26 min (UV_(254 nm)); mass calculatedfor formula C₁₁H₁₃N₃O₂S 251.1, observed LCMS m/z 252.1 (M+H).

Part B:

Compound 60 was prepared using the hydrolysis condition described inexample 1 part H. HPLC-MS t_(R)=0.86 min (UV_(254 nm)); mass calculatedfor formula C₉H₉N₃O₂S 223.0, observed LCMS m/z 224.1 (M+H).

Part C:

Compound 61 was synthesized using the peptide coupling conditionsdescribed in example 1 part I. HPLC-MS t_(R)=1.49 min (UV_(254 nm));mass calculated for formula C₁₉H₂₇N₅O₃S 405.2, observed LCMS m/z 406.2(M+1H).

Part D:

Compound 62 was synthesized using the oxidation condition described inexample 1 part D. HPLC-MS t_(R)=1.31 min (UV_(254 nm)); mass calculatedfor formula C₁₉H₂₇N₅O₅S 437.2, observed LCMS m/z 438.2 (M+H).

Part E.

Compound 63 was prepared using the condition described in example 1 partE. HPLC-MS t_(R)=1.01 min (UV_(254 nm)); mass calculated for formulaC₁₈H₂₆N₆O₃ 374.2, observed LCMS m/z 375.2 (M+H)

Part F:

Compound 64 was synthesized using the condition described in example 1part F. HPLC-MS t_(R)=1.18 min (UV_(254 nm)); mass calculated forformula C₁₈H₂₅BrN₆O₃ 452.1 observed LCMS m/z 453.1 (M+H).

Part G:

Compound 65 was synthesized using the coupling condition described inexample 1 part G. HPLC-MS t_(R)=1.42 min (UV_(254 nm)); mass calculatedfor formula C23H₃₀N₆O₃S 470.2, observed LCMS m/z 471.2 (M+H).

Part H:

Compound 66 was synthesized using the deprotecting condition describedin example 1 part J. HPLC-MS t_(R)=0.72 min (UV_(254 nm)); masscalculated for formula C₁₈H₂₂N₆OS 370.2, observed LCMS m/z 371.2 (M+H).

EXAMPLE 13

Compound 69 was prepared in example 1 part F.Part A:

Compound 67 was synthesized using the coupling condition described inexample 1 part G. HPLC-MS t_(R)=2.09 min (UV_(254 nm)); mass calculatedfor formula C₁₀H₈S 160.0, observed LCMS m/z 161.0 (M+H).

Part B:

Compound 67 (160 mg, 1.0 mmol) was dissolved in dry THF (10 mL) andcooled down to 0° C. To this mixture, n-BuLi (2.5 M in hexane, 0.44 mL,1.1 mmol) was added at 0° C. and stirred at room temperature for 2hours, The mixture was cooled down to −78° C. and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (372 mg, 2.0 mmol)was added. The mixture was warmed up to room temperature slowly andstirred overnight. After work up, the crude product was purified withflash chromatography column (Ethyl acetate/hexane=5/95) gave the product68 (201 mg). HPLC-MS t_(R)=2.42 min (UV_(254 nm)); mass calculated forformula C₁₆H₁₉BO₂S 286.1, observed LCMS m/z 287.1 (M+H).

Part C:

Compound 70 was synthesized using the coupling condition described inexample 1 part G. HPLC-MS t_(R)=1.87 min (UV_(254 nm)); mass calculatedfor formula C₂₆H₂₉N₅O₂S 475.2, observed LCMS m/z 476.2 (M+H).

Part D:

Compound 71 was synthesized using the deprotection condition describedin example 1 part J. HPLC-MS t_(R)=0.97 min (UV_(254 nm)); masscalculated for formula C₁₈H₂₂N₆OS 375.2, observed LCMS m/z 376.2 (M+H).

EXAMPLE 14

By essentially the same procedure given in Preparative Example 13,compounds given in Column 2 of Table 4 can be prepared. TABLE 4 MS Ex-Exact m/z HPLC ample Structure mass (M + H) MS t_(R) 72

409.1 410.1 0.99 73

376.1 377.1 0.95 74

379.2 380.2 0.85

EXAMPLE 15

Part A:

Compound Ethyl thiophene-3-carboxylate (4.0 g, 25.6 mmol) was dissolvedin acetic acid (50 mL) and Br₂ (4.06 g) in acetic acid (10 mL) was addeddropwise. After addition, the mixture was heated up to 60° C. andstirred for 40 hour. The mixture was concentrated and purified by flashchromatography column (EtOAc/hexane=10/90) gave the product 75 asyellowish oil (4.8 g). HPLC-MS t_(R)=2.08 min (UV_(254 nm)); masscalculated for formula C₇H₇BrO₂S 233.9, observed LCMS m/z 234.9 (M+H).

Part B:

Compound 75 (50 mg, 0.21 mmol), bis(pinacolato)diboron (61 mg, 0.24mmol), Pd(dppf)Cl₂ (8 mg, 0.01 mmol) and KOAc (40 mg, 0.4 mmol) wasmixed in DMSO (2 mL) in a vial under Argon and the vial was sealed underArgon. The resulting mixture was heated to 80° C. and stirred overnight,After cooling to room temperature, the mixture was diluted with EtOAc(50 mL) and washed with water, brine and dried over Na₂SO₄. Afterconcentration, the product was purified by column (EtOAc/hexane=20/80)gave the product 76 as semi-solid (39 mg). HPLC-MS t_(R)=2.27 min(UV_(254 nm)); mass calculated for formula C13H₁₉BO₄S 282.1, observedLCMS m/z 283.1 (M+H).

Part C:

Compound 77 was synthesized using the coupling condition described inexample 1 part G. HPLC-MS t_(R)=1.65 min (UV_(254 nm)); mass calculatedfor formula C₂₃H₂₉N₅O₄S 471.2, observed LCMS m/z 472.1 (M+H).

Part D:

Compound 78 was synthesized using the coupling condition described inexample 1 part G. HPLC-MS t_(R)=0.84 min (UV_(254 nm)); mass calculatedfor formula C₁₈H₂₁N₅O₂S 371.1, observed LCMS m/z 372.1 (M+H).

EXAMPLE 16

Part A:

Compound 77 (0.25 mmol, 120 mg) dissolved in THF (10 mL) and LiOH (20mg, 0.5 mmol, 10 mL) was added to the above solution and stirred at roomtemperature for 6 hrs, concentration and neutralization to pH 4 withresulted in white precipitate. This precipitate was extracted in toethyl acetate and organic layer dried over anhydrous sodium sulfate,filtered and organic layer evaporated under vacuum to give the freecarboxylic acid (79)

Part B:

The compound 79 was used in this step with out purification. Compound 79(0.25 mmol, 110 mg) N,N-Dimethylamine (1 mmol), DIEA (1.76 mL, 1 mmol)and HATU (0.38 g, 1 mmol) in DMF (2 mL) was stirred at 0° C. overnightAfter concentration, the residue was taken up with water (6 mL), thesolid was extracted in to ethyl acetate, washed with brine and driedover anhydrous sodium sulfate. Evaporation of organic solvent andfollowed by HPLC purification resulted in compound 80 as white solid (90mg). HPLC-MS t_(R)=min (UV_(254 nm)); mass calculated for formulaC₂₃H₃₀N₆O₃, 470.21 observed LCMS m/z 471.20 (M+H).

Part C:

Compound 81 was synthesized by the deprotection of Boc group fromcompound 80 using condition described in example 1 part J. HPLC-MSt_(R)=min (UV_(254 nm)); mass calculated for formula C₁₈H₂₂N₆OS 370.16,observed LCMS m/z 371.20 (M+H).

EXAMPLE 17

By essentially the same procedure given in Preparative Example 16,compounds given in Column 2 of Table 5 can be prepared. TABLE 5 MS Ex-Exact m/z HPLC ample Structure mass (M + H) MS t_(R) 82

356.1 357.1 0.66

EXAMPLE 18

Part A:

Compound 83 was synthesized by the deprotection of Boc group fromcompound 79 using condition described in example 1 part J. HPLC-MSt_(R)=0.68 min (UV_(254 nm)); mass calculated for formula C₁₆H₁₇NSO₂S343.1, observed LCMS m/z 344.1 (M+H).

EXAMPLE 19

Part A:

Compound 84 was prepared using the same conditions described in part Cof Example 1. HPLC-MS t_(R)=1.78 min (UV_(254 nm)); mass calculated forformula C₁₂H₇Cl₂N₃ 263.0, observed LCMS m/z 264.1 (M+H).

Part B:

The compound 84 (480 mg, 1.82 mmol) from part A was dissolved in NMP (5ml) and amine (400 mg, 2.0 mmol), K₂CO₃ (276 mg, 2.0 mmol) were added.The mixture was heated up to 100° C. and stirred for 1 day. Aftercooling to room temperature, the mixture was diluted with EtOAc andwashed with water and brine. After concentration, the residue waspurified with column (silica gel, EtOAc/Hexane=50/50) gave the product85 (461 mg) as solid. HPLC-MS t_(R)=1.77 min (UV_(254 nm)); masscalculated for formula C₂₂H₂₆ClN₅O₂ 427.2, observed LCMS m/z 428.2(M+H).

Part C:

The compound 86 was prepared using the same bromination conditionsdescribed in part F of Example 1. HPLC-MS t_(R)=2.47 min (UV_(254 nm));mass calculated for formula C₂₂H₂₅BrClN₅O₂ 505.1, observed LCMS m/z506.0 (M+H)+

Part D:

To a 25 ml round bottom flask charged with compound 86 (125 mg, 0.25mmol), Zn(CN)₂ (60 mg, 0.5 mmol), and Pd(PPh₃)₄ (55 mg, 0.05 mmol) wasadded a DMF (5 mL). The mixture was thoroughly degassed by alternatelyconnected the flask to vacuum and Argon, This resulting mixture was thenheated at 80° C. overnight. After cooling to room temperature, it wasdiluted with EtOAc (40 ml) and filtered through celite. Afterconcentration, the residue was purified with column (silica gel,EtOAc/hexane=30/70) to give the product 87 (82 mg) as oil. HPLC-MSt_(R)=2.37 min (UV_(254 nm)); mass calculated for formula C23H₂₅ClN₆O₂452.2, observed LCMS m/z 453.2 (M+H).

Part E:

To the compound 87 (20 mg) in 20 vial, H₂SO₄ (0.5 mL) was added and theresulting mixture was stirred for 1 hour at room temperature. Then, ice(2 g) was added and the pH was adjusted to 9 with 50% NaOH. The solidwas collected with filtration and purified with Prep-LC gave the product88. HPLC-MS t_(R)=1.24 min (UV_(254 nm)); mass calculated for formulaC₁₈H₁₉ClN₆O 370.1, observed LCMS m/z 371.2 (M+H).

EXAMPLE 20

Part A:

Compound 87 (20 mg, 0.044 mmol) was dissolved in CHCl₃ (5 mL) and NBS(12 mg, 0.066 mmol) was added. The mixture was stirred at roomtemperature for 1 hour, then heated up to 50° C. and stirred overnightAfter concentration, the residue was purified with column (silica gel,EtOAc/hexane=30/70) to give the product 89 (16 mg) as oil. HPLC-MSt_(R)=2.48 min (UV_(254 nm)); mass calculated for formula C₂₃H₂₄BrClN₆O₂530.1, observed LCMS m/z 531.2 (M+H).

Part B:

Compound 90 was synthesized with the same condition described in part Eof example 19. HPLC-MS t_(R)=1.24 min (UV_(254 nm)); mass calculated forformula C₁₈H₁₈BrClN₆O 448.0, observed LCMS m/z 449.0 (M+H).

Assays:

CHK1 SPA Assay

An in vitro assay was developed that utilizes recombinant His-CHK1expressed in the baculovirus expression system as an enzyme source and abiotinylated peptide based on CDC25C as substrate(biotin-RSGLYRSPSMPENLNRPR).

Materials and Reagents:

1) CDC25C Ser 216 C-term Biotinylated peptide substrate (25 mg), storedat −20° C., Custom Synthesis by Research Genetics:biotin-RSGLYRSPSMPENLNRPR 2595.4 MW

2) His-CHK1 In House lot P976, 235 μg/mL, stored at −80° C.

3) D-PBS (without CaCl and MgCl): GIBCO, Cat.# 14190-144

4) SPA beads: Amersham, Cat.# SPQ0032: 500 mg/vial

-   -   Add 10 mls of D-PBS to 500 mg of SPA beads to make a working        concentration of 50 mg/ml. Store at 4° C. Use within 2 week        after hydration.        5) 96-Well White Microplate with Bonded GF/B filter: Packard,        Cat.# 6005177        6) Top seal-A 96 well Adhesive Film: Perkin Elmer, Cat.# 6005185        7) 96-well Non-Binding White Polystyrene Plate: Corning, Cat. #        6005177        8) MgCl₂: Sigma, Cat.# M-8266        9) DTT: Promega, Cat.# V3155        10) ATP, stored at 4° C.: Sigma, Cat.# A-5394        11) γ³³P-ATP, 1000-3000 Ci/mMol: Amersham, Cat.# AH9968        12) NaCl: Fisher Scientific, Cat.# BP358-212        13) H₃PO₄ 85% Fisher, Cat.#A242-500        14) Tris-HCL pH 8.0: Bio-Whittaker, Cat. # 16-015V        15) Staurosporine, 100 ug: CALBIOCHEM. Cat. # 569397        16) Hypure Cell Culture Grade Water, 500 mL: HyClone, Cat.#        SH30529.02        Reaction Mixtures:        1) Kinase Buffer: 50 mM Tris pH 8.0; 10 mM MgCl₂; 1 mM DTT        2) His-CHK1, In House Lot P976, MW ˜30 KDa, stored at −80° C.

6 nM is required to yield positive controls of ˜5,000 CPM. For 1 plate(100 rxn): dilute 8 μL of 235 ug/mL (7.83 uM) stock in 2 mL KinaseBuffer. This makes a 31 nM mixture. Add 20 μL/well. This makes a finalreaction concentration of 6 nM.

3) CDC25C Biotinylated peptide.

Dilute CDC25C to 1 mg/mL (385 uM) stock and store at −20° C. For 1 plate(100 rxn): dilute 10 μL of 1 mg/mL peptide stock in 2 ml Kinase Buffer.This gives a 1.925 uM mix. Add 20 μL/rxn. This makes a final reactionconcentration of 385 nM

4) ATP Mix.

For 1 plate (100 rxn): dilute 10 μL of 1 mM ATP (cold) stock and 2 μLfresh P33-ATP (20 μCi) in 5 ml Kinase Buffer. This gives a 2 uM ATP(cold) solution; add 50 μl/well to start the reaction. Final volume is100 μl/rxn so the final reaction concentrations will be 1 uM ATP (cold)and 0.2 μCi/reaction.

5) Stop Solution:

For 1 plate add: To 10 mL Wash Buffer 2 (2M NaCl 1% H₃PO₄): 1 mL SPAbead slurry (50 mg); Add 100 μL/well

6) Wash buffer 1: 2 M NaCl

7) Wash buffer 2: 2 M NaCl, 1% H₃PO₄

Assay Procedure: Assay Final Component Concentration Volume CHK 1 6 nM20 μl/rxn Compound — 10 μl/rxn (10% DMSO) CDC25C 0.385 μM 20 μl/rxnγ³³P-ATP 0.2 μCi/rxn 50 μl/rxn Cold ATP 1 μM Stop solution 0.5 mg/rxn100 μl/rxn* SPA beads 200 μl/rxn***Total reaction volume for assay.**Final reaction volume at termination of reaction (after addition ofstop solution).1) Dilute compounds to desired concentrations in water/10% DMSO—thiswill give a final DMSO concentration of 1% in the reaction. Dispense 10μl/rxn to appropriate wells. Add 10 μL 10% DMSO to positive(CHK1+CDC25C+ATP) and negative (CHK1+ATP only) control wells.2) Thaw enzyme on ice—dilute enzyme to proper concentration in kinasebuffer (see Reaction Mixtures) and dispense 20 μl to each well.3) Thaw the Biotinylated substrate on ice and dilute in kinase buffer(see Reaction Mixtures). Add 20 μL/well except to negative controlwells. Instead, add 20 μL Kinase Buffer to these wells.4) Dilute ATP (cold) and P33-ATP in kinase buffer (see ReactionMixtures). Add 50 μL/well to start the reaction.5) Allow the reaction to run for 2 hours at room temperature.6) Stop reaction by adding 100 μL of the SPA beads/stop solution (seeReaction Mixtures) and leave to incubate for 15 minutes before harvest7) Place a blank Packard GF/B filter plate into the vacuum filter device(Packard plate harvester) and aspirate 200 mL water through to wet thesystem.8) Take out the blank and put in the Packard GF/B filter plate.9) Aspirate the reaction through the filter plate.10) Wash: 200 ml each wash; 1× with 2M NaCl; 1× with 2M NaCl/1% H₃PO₄11) Allow filter plate to dry 15 min.12) Put TopSeal-A adhesive on top of filter plate.13) Run filter plate in Top Count

Settings:

-   -   Data mode: CPM    -   Radio nuclide: Manual SPA:P33    -   Scintillator: Liq/plast    -   Energy Range Low

IC₅₀ DETERMINATIONS. Dose-response curves were plotted from inhibitiondata generated, each in duplicate, from 8 point serial dilutions ofinhibitory compounds. Concentration of compound was plotted against %kinase activity, calculated by CPM of treated samples divided by CPM ofuntreated samples. To generate IC₅₀ values, the dose-response curveswere then fitted to a standard sigmoidal curve and IC₅₀ values werederived by nonlinear regression analysis, IC₅₀ values for some compoundsof the present invention determined according to the above method areset forth in Table 6 below. As demonstrated above by the assay values,the compounds of the present invention exhibit good Chk1 inhibitoryproperties.

CDK2 Assay:

BACULOVIRUS CONSTRUCTIONS: Cyclin E was cloned into pVL1393 (Pharmingen,La Jolla, Calif.) by PCR, with the addition of 5 histidine residues atthe amino-terminal end to allow purification on nickel resin. Theexpressed protein was approximately 45 kDa. CDK2 was cloned into pVL1393by PCR, with the addition of a haemaglutinin epitope tag at thecarboxy-terminal end (YDVPDYAS). The expressed protein was approximately34 kDa in size.

ENZYME PRODUCTION: Recombinant baculoviruses expressing cyclin E andCDK2 were co-infected into SF9 cells at an equal multiplicity ofinfection (MOI=5), for 48 hrs. Cells were harvested by centrifugation at1000 RPM for 10 minutes, then pellets lysed on ice for 30 minutes infive times the pellet volume of lysis buffer containing 50 mM Tris pH8.0, 150 mM NaCl, 1% NP40, 1 mM DTT and protease inhibitors (RocheDiagnostics GmbH, Mannheim, Germany). Lysates were spun down at 15000RPM for 10 minutes and the supernatant retained. 5 ml of nickel beads(for one liter of SF9 cells) were washed three times in lysis buffer(Qiagen GmbH, Germany). Imidazole was added to the baculovirussupernatant to a final concentration of 20 mM, then incubated with thenickel beads for 45 minutes at 4° C. Proteins were eluted with lysisbuffer containing 250 mM imidazole. Eluate was dialyzed overnight in 2liters of kinase buffer containing 50 mM Tris pH 8.0, 1 mM DTT, 10 mMMgCl2, 100 uM sodium orthovanadate and 20% glycerol. Enzyme was storedin aliquots at −70° C.

IN VITRO KINASE ASSAY: Cyclin E/CDK2 kinase assays were performed in lowprotein binding 96-well plates (Corning Inc, Corning, N.Y.). Enzyme wasdiluted to a final concentration of 50 μg/ml in kinase buffer containing50 mM Tris pH 8.0, 10 mM MgCl₂, 1 mM DTT, and 0.1 mM sodiumorthovanadate. The substrate used in these reactions was a biotinylatedpeptide derived from Histone H1 (from Amersham, UK). The substrate wasthawed on ice and diluted to 2 μM in kinase buffer. Compounds werediluted in 10% DMSO to desirable concentrations. For each kinasereaction, 20 μl of the 50 μg/ml enzyme solution (1 μg of enzyme) and 20μl of the 2 μM substrate solution were mixed, then combined with 10 μlof diluted compound in each well for testing. The kinase reaction wasstarted by addition of 50 μl of 2 μM ATP and 0.1 μCi of 33P-ATP (fromAmersham, UK). The reaction was allowed to run for 1 hour at roomtemperature. The reaction was stopped by adding 200 μl of stop buffercontaining 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, and 5 mg/mlstreptavidine coated SPA beads (from Amersham, UK) for 15 minutes. TheSPA beads were then captured onto a 96-well GF/B filter plate(Packard/Perkin Elmer Life Sciences) using a Filtermate universalharvester (Packard/Perkin Elmer Life Sciences.). Non-specific signalswere eliminated by washing the beads twice with 2M NaCl then twice with2 M NaCl with 1% phosphoric acid. The radioactive signal was thenmeasured using a TopCount 96 well liquid scintillation counter (fromPackard/Perkin Elmer Life Sciences).

IC₅₀ DETERMINATIONS: Dose-response curves were plotted from inhibitiondata generated, each in duplicate, from 8 point serial dilutions ofinhibitory compounds. Concentration of compound was plotted against %kinase activity, calculated by CPM of treated samples divided by CPM ofuntreated samples. To generate IC₅₀ values, the dose-response curveswere then fitted to a standard sigmoidal curve and IC₅₀ values werederived by nonlinear regression analysis. Table 6 shows the activitydata for an illustrative representative list of compounds of theinvention. TABLE 6 CHK1 CHK2 assay assay Structure IC₅₀ nM IC₅₀ nM

187

216

139

84 4

39 4

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound of Formula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof, wherein: R is selected from the group consisting of H, halo,amino, alkyl, aryl, heteroaryl, heteroarylalkyl-, cycloalkyl,cycloalkylalkyl-, cycloalkenyl, cycloalkenylalkyl-, arylalkyl-,heterocyclyl, heterocyclylalkyl-, heterocyclenyl, heterocyclenylalkyl-,alkenyl-, alkynyl-, and —CN, wherein each of said alkyl, aryl,heteroaryl, heterocyclyl and cycloalkyl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different each moiety being independently selected fromhalo, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵; R¹ isselected from the group consisting of H, alkyl, aryl, arylalkyl-,heteroaryl, heteroarylalkyl-, cycloalkenyl, cycloalkenylalkyl,arylalkyl-, heterocyclyl, heterocyclylalkyl-, heterocyclenyl,heterocyclenylalkyl, and —C(O)—N(R¹⁴R¹⁵), wherein each of said alkyl,aryl, heteroaryl, heterocyclyl and cycloalkyl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different each moiety being independently selected fromhalo, alkyl, aryl, cyano, —OR¹⁴, —SR¹⁴, —S(O)R¹⁴, —S(O₂)R¹⁴, —N(R¹⁴R¹⁵),—C(O)O-alkyl, —C(O)—N(R¹⁴R¹⁵), —N(R¹⁴)S(O₂)R¹⁵, and —N(R¹⁴)C(O)R¹⁵; R²is selected from the group consisting of H, halo, amino, alkyl, aryl,heteroaryl, heteroarylalkyl-, cycloalkyl, cycloalkylalkyl-,cycloalkenyl, cycloalkenylalkyl, arylalkyl-, heterocyclyl,heterocyclylalkyl-, heterocyclenyl, heterocyclenylalkyl, alkenyl,alkynyl, and —CN, wherein each of said alkyl, aryl, heteroaryl,heterocyclyl and cycloalkyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different each moiety being independently selected from halo,alkyl, cyano, —N(R¹⁴R¹⁵), C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵; R³ isselected from the group consisting of H, alkyl, amino, aryl, heteroaryl,heteroarylalkyl-, cycloalkyl, cycloalkylalkyl-, cycloalkenyl,cycloalkenylalkyl, arylalkyl-, heterocyclyl, heterocyclylalkyl-,heterocyclenyl, heterocyclenylalkyl, alkenyl, alkynyl, —C(O)—N(R¹⁴R¹⁵)and —CN, wherein each of said alkyl, aryl, heteroaryl, heterocyclyl andcycloalkyl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵; X is selected from the groupconsisting of a covalent bond, —C(O)—NR¹⁴, —S(O₂)N(R¹⁴)—,—N(R¹⁴)—C(O)—N(R¹⁵), —C(O)—O—, —O—C(O)—,—O—C(O)—N(R¹⁴)—N(R¹⁴—C(R¹⁴R¹⁵)—, —O—, —S—, —(O)—, and —S(O₂)—, or themoiety

 where n1 is 1-3; R⁴ is selected from the group consisting of alkyl,—C(O)O-alkyl, heterocyclyl, aryl, and amino, wherein each of said alkyl,aryl and heterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵); R⁶ is H, alkyl, cycloalkyl or aryl, wherein eachof said alkyl, aryl and cycloalkyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from halo,alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ isH, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryl andcycloalkyl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different, eachmoiety being independently selected from halo, alkyl, cyano, acyl,hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-,alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —O(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; and R¹⁴ and R¹⁵ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl; with the proviso that the invention excludes thefollowing compounds:


2. The compound of claim 1, wherein R is H, alkyl, aryl, heteroaryl oramino.
 3. The compound of claim 1, wherein R is H.
 4. The compound ofclaim 1, wherein R¹ is selected from the group consisting of H,unsubstituted aryl, aryl substituted with one or more moieties selectedfrom the group consisting of halo, alkyl, cyano, alkoxy, aryl,alkoxycarbonyl, carboxy, —CF₃, —OCF3, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵, unsubstituted heteroaryl and heteroaryl substituted withone or more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 5. The compound of claim 1, whereinR¹ is H.
 6. The compound of claim 1, wherein R¹ is unsubstituted aryl.7. The compound of claim 1, wherein R¹ is aryl substituted with one ormore moieties selected from the group consisting of halo, alkyl, cyano,alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 8. The compound of claim 1, whereinR¹ is aryl substituted with one or more moieties selected from the groupconsisting of halo, alkyl, alkoxy, aryl, —CF₃, —OCF₃,


9. The compound of claim 1, wherein R¹ is unsubstituted heteroaryl. 10.The compound of claim 1, wherein R¹ is heteroaryl substituted with oneor more moieties selected from the group consisting of halo, alkyl,cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 11. The compound of claim 1, whereinR¹ is a pyrazolyl substituted with one or more moieties selected fromthe group consisting of halo, alkyl, cyano, alkoxy, aryl,alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵.
 12. The compound of claim 1, wherein R¹ is a thiophenylsubstituted with one or more moieties selected from the group consistingof halo, alkyl, cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃,—OCF₃, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 13. The compoundof claim 1, wherein R¹ is a benzothiophenyl substituted with one or moremoieties selected from the group consisting of halo, alkyl, cyano,alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 14. The compound of claim 1, whereinR¹ is a pyrazolyl substituted with one or more moieties selected fromthe group consisting of methyl, cyano, phenyl, 4-chlorophenyl, —CO₂Et,—CO₂H and —C(O)NMe₂.
 15. The compound of claim 1, wherein R¹ is athiophenyl substituted with one or more moieties selected from the groupconsisting of methyl, cyano, phenyl, 4-chlorophenyl, —CO₂Et, —CO₂H and—C(O)NMe₂.
 16. The compound of claim 1, wherein R¹ is a benzothiophenylsubstituted with one or more moieties selected from the group consistingof methyl, cyano, phenyl, 4-chlorophenyl, —CO₂Et, —CO₂H and —C(O)NMe₂.17. The compound of claim 1, wherein R¹ is pyrazolyl substituted withalkyl.
 18. The compound of claim 1, wherein R¹ is 1-methyl-pyrazol-4-yl.19. The compound of claim 1, wherein R² is H, unsubstituted aryl, arylsubstituted with one or more moieties selected from the group consistingof halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵,unsubstituted heteroaryl and heteroaryl substituted with one or moremoieties selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 20. The compound ofclaim 1, wherein R² is H.
 21. The compound of claim 1, wherein R² isunsubstituted aryl.
 22. The compound of claim 1, wherein R² is arylsubstituted with one or more moieties selected from the group consistingof halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R′″.23. The compound of claim 1, wherein R² is unsubstituted heteroaryl. 24.The compound of claim 1, wherein R² is heteroaryl substituted with oneor more moieties selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 25. The compoundof claim 1, wherein R² is selected from the group consisting of

where R¹⁴ is as discussed above, n is 0-3 and R¹⁶ is selected from thegroup consisting of alkyl, aryl, cycloalkyl and heteroaryl.
 26. Thecompound of claim 1, wherein R² is pyrazolyl.
 27. The compound of claim1, wherein R² is pyrazolyl substituted with alkyl.
 28. The compound ofclaim 1, wherein R² is 1-methyl-pyrazol-4-yl.
 29. The compound of claim1, wherein R³ is selected from H, unsubstituted aryl, aryl substitutedwith one or more moieties selected from the group consisting of halo,alkyl, cyano, alkoxy, aryl, alkoxycarbonyl, carboxy, —CF₃, —OCF₃,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, unsubstituted heteroaryland heteroaryl substituted with one or more moieties selected from thegroup consisting of halo, alkyl, cyano, alkoxy, aryl, alkoxycarbonyl,carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.30. The compound of claim 1, wherein R³ is H.
 31. The compound of claim1, wherein R³ is unsubstituted aryl.
 32. The compound of claim 1,wherein R³ is aryl substituted with one or more moieties selected fromthe group consisting of halo, alkyl, cyano, alkoxy, aryl,alkoxycarbonyl, carboxy, —CF₃, —OCF₃, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵.
 33. The compound of claim 1, wherein R³ is arylsubstituted with one or more moieties selected from the group consistingof methoxy and carbethoxy.
 34. The compound of claim 1, wherein R³ isunsubstituted heteroaryl.
 35. The compound of claim 1, wherein R³ isheteroaryl substituted with one or more moieties selected from the groupconsisting of halo, alkyl, cyano, alkoxy, aryl, alkoxycarbonyl, carboxy,—CF₃, —OCF₃, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵.
 36. Thecompound of claim 1, wherein R³ is pyrazolyl.
 37. The compound of claim1, wherein R³ is pyrazolyl substituted with alkyl.
 38. The compound ofclaim 1, wherein R³ is 1-methyl-pyrazol-4-yl.
 39. The compound of claim1, wherein X is selected from the group consisting of a bond,—C(O)—NR¹⁴, —S(O₂)N(R¹⁴)—, —C(O)—O—, and —C(R¹⁴R¹⁵)—.
 40. The compoundof claim 1, wherein R³ is selected from the group consisting of:

wherein R¹⁴ n and R¹⁶ are as described earlier.
 41. The compound ofclaim 1, wherein X is a covalent bond.
 42. The compound of claim 1,wherein

-X—R⁴ is

-CH₂—C(O)—NH(heterocyclyl).
 43. The compound of claim 1, wherein

is:


44. The compound of claim 1, wherein R⁴ is selected from the groupconsisting of alkyl, —C(O)O-alkyl, heterocyclyl, and aryl, wherein eachof said alkyl, aryl and heterocyclyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different each moiety being independently selected from halo,alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —OR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).
 45. The compound of claim 1, wherein R⁴ isselected from the group consisting of pyrrolidinyl, piperidinyl, phenyland ethoxycarbonyl, wherein each of said pyrrolidinyl, piperidinyl andphenyl can be unsubstituted or optionally independently substituted withone or more moieties which can be the same or different each moietybeing independently selected from halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —OR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).
 46. The compound of claim 1,wherein R⁴ is selected from the group consisting of: alkyl,

wherein R⁸ is selected from the group consisting of H, NH₂, N(R¹⁴R¹⁵)and (R¹⁴R¹⁵)N—N(R¹⁴R¹⁵); n is 0-2; and R⁹, R¹⁰, R¹¹ and R¹² can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.47. The compound of claim 1, wherein R⁴ is pyrrolidinyl wherein saidpyrrolidinyl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵,—C(O)O-alkyl, —OR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).
 48. Thecompound of claim 1, wherein R⁴ is piperidinyl wherein said piperidinylcan be unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, OR¹⁴,—O—CO—N(R¹⁴R¹⁵) and —N(R¹⁴)—CO—N(R¹⁴R¹⁵).
 49. The compound of claim 1,wherein R⁴ is phenyl wherein said phenyl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different each moiety being independently selected fromhalo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵—C(O)O-alkyl, —OR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵).
 50. The compound of claim 1, wherein R⁴ isethoxycarbonyl.
 51. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═R¹═H, X is a covalent bond, R³ and R⁴ are bothunsubstituted pyrazolyl, wherein said pyrazolyl can be unsubstituted orsubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from the group consisting ofhalo, alkyl, cyano, —N(R¹⁴R¹⁵)—C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵,wherein R⁶ is H, alkyl, cycloalkyl or aryl, wherein each of said alkyl,aryl and cycloalkyl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from halo, alkyl,cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃5dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ isH, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryl andcycloalkyl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different, eachmoiety being independently selected from halo, alkyl, cyano, acyl,hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-,alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; and R¹⁴ and R¹⁵ canbe the same or different, each being independently selected from thegroup consisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 52. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR^(p) is heteroaryl, R═R¹═H, X is a covalent bond, R³ and R⁴ are botharyl, wherein said each of aryl and heteroaryl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different each moiety being independently selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵)and —N(R¹⁴)C(O)R¹⁵, wherein R⁶ is H, alkyl, cycloalkyl or aryl, whereineach of said alkyl, aryl and cycloalkyl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different, each moiety being independently selected fromhalo, alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃,—CF₃, dialkylamino, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-,—NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl;and R⁷ is H, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryland cycloalkyl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from halo, alkyl,cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃,dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R¹⁴ andR¹⁵ can be the same or different, each being independently selected fromthe group consisting of H, alkyl, aryl, heteroaryl, arylalkyl,cycloalkyl, heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl,—OR⁶, —OCF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂,wherein each of said alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from halo, alkyl, cyano, acyl,hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶,—S(O₂)R⁶, —S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,and —C(O)O-heteroaryl.
 53. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═R¹═H, X is a covalent bond, R³ is aryl and R⁴ is aheterocyclyl, wherein each of said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups; R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴—SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 54. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═R¹═H, X is a covalent bond, R³ is aryl and R⁴ is aheterocyclyl, wherein each of said pyrazolyl and aryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, wherein R⁶ is H, alkyl,cycloalkyl or aryl, wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R^(15)— and —N(R) ¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can bethe same or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 55. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═R¹═H, X is a covalent bond, R³ is heteroaryl and R⁴is a heterocyclyl, wherein each of said pyrazolyl and heteroaryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups and R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴,—SR¹⁴—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can bethe same or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 56. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═H, R¹ is aryl, X is a covalent bond, R³ is aryland R⁴ is a heterocyclyl, wherein each of said aryl and heteroaryl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, and R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —O(O)O-aryl, and—C(O)O-heteroaryl.
 57. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═H, R¹ is heteroaryl, X is a covalent bond, R³ isaryl and R⁴ is a heterocyclyl, wherein each of said aryl and heteroarylcan be unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, and R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —O(CO)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR^(p), —OCF₃,—N(R⁶R⁷), —SR⁶—S(O₂)R⁶, —ON, —S(O₂)N(R6R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 58. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a heteroaryl, R═H, R¹ is heteroaryl, X is a covalent bond, R³ isheteroaryl and R⁴ is a heterocyclyl, wherein each of said heteroarylscan be unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵ wherein said heterocyclylcan be unsubstituted or optionally substituted with one or moreindependently selected R⁸ groups, and R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃₁ dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴—SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 59. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═H, R¹ is aryl, X is a covalent bond, R³ is aryl andR⁴ is a heterocyclyl, wherein each of said pyrazolyl and aryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from the group consisting of halo, alkyl, cyano,—N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, and R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be the sameor different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 60. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is a pyrazolyl, R═H, R¹ is heteroaryl, X is a covalent bond, R³ isheteroaryl and R⁴ is a heterocyclyl, wherein each of said pyrazolyl andheteroaryl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, and R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵). —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylheterocyclyl, acyl, halo hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 61. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR² is 1-methyl-pyrazol-4-yl, R═H, R¹ is a heteroaryl, X is a covalentbond, R³ is heteroaryl and R⁴ is a heterocyclyl, wherein each of saidheteroaryls can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different each moietybeing independently selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵, wherein saidheterocyclyl can be unsubstituted or optionally substituted with one ormore independently selected R⁸ groups, and R⁶ is H, alkyl, cycloalkyl oraryl, wherein each of said alkyl, aryl and cycloalkyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R³ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵)—N(R¹⁴)CO)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 62. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹═R²=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, R³ is heteroaryland R⁴ is a heterocyclyl, wherein said heteroaryl can be unsubstitutedor substituted with one or more moieties which can be the same ordifferent each moiety being independently selected from the groupconsisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵, wherein said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, and R⁶ is H, alkyl, cycloalkyl or aryl, wherein each of saidalkyl, aryl and cycloalkyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from halo,alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃,dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ isH, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryl andcycloalkyl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different, eachmoiety being independently selected from halo, alkyl, cyano, acyl,hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-,alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O R¹⁵), —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 63. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹═R²=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, R³ is heteroaryland R⁴ is a heterocyclyl, wherein said heteroaryl can be unsubstitutedor substituted with one or more moieties which can be the same ordifferent each moiety being independently selected from the groupconsisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and—N(R¹⁴)C(O)R¹⁵, wherein said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, and R⁶ is H, alkyl, cycloalkyl or aryl, wherein each of saidalkyl, aryl and cycloalkyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from halo,alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃,dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ isH, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryl andcycloalkyl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different, eachmoiety being independently selected from halo, alkyl, cyano, acyl,hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-,alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵)—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃₁—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 64. A compound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹═R²═R³=1-methyl-pyrazol-4-yl R═H, X is a covalent bond, and R⁴ is aheterocyclyl, wherein said heterocyclyl can be unsubstituted oroptionally substituted with one or more independently selected R⁸groups, wherein R⁸ is selected from the group consisting of halo, alkyl,cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl,—C(O)O-heteroaryl, —OR⁴, —SR¹⁴ ₂—O—CO—N(R¹⁴R¹⁵)— and—N(R¹⁴)—CO—N(R¹⁴R¹⁵); R¹⁴ and R¹⁵ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl,aryl, heteroaryl, arylalkyl, cycloalkyl, heterocyclyl, acyl, halo,hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃, —N(R⁶R⁷), —SR⁶,—S(O₂)R^(f6), —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each of said alkyl,aryl, heteroaryl, cycloalkyl and heterocyclyl can be unsubstituted oroptionally independently substituted with one or more moieties which canbe the same or different each moiety being independently selected fromhalo, alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁶ is H, alkyl,cycloalkyl or aryl, wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; and R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl.
 65. A compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR1=R²═R³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, and R⁴ is apiperidinyl, wherein said piperidinyl can be unsubstituted or optionallysubstituted with independently selected R⁸ groups, wherein R⁸ isselected from the group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴,—SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl; R⁶ is H, alkyl, cycloalkyl or aryl, wherein each ofsaid alkyl, aryl and cycloalkyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from halo,alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃,dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-,—NO₂₁—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl;and R⁷ is H, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryland cycloalkyl can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from halo, alkyl,cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃,dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl.
 66. Acompound of the formula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR1=R²═R³=1-methyl-pyrazol-4-yl, R—H, X is a covalent bond, and R⁴ is apyrrolidinyl, wherein said pyrrolidinyl can be unsubstituted oroptionally substituted with independently selected R⁸ groups, wherein R⁸is selected from the group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵),—C(O)—N(R¹⁴R¹⁵), —S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴,—SR¹⁴, —O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR^(n), —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, —OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl; R⁶ is H, alkyl, cycloalkyl or aryl, wherein each ofsaid alkyl, aryl and cycloalkyl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from halo,alkyl, cyano, acyl, hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃,dialkylamino-, alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂,—C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; and R⁷is H, alkyl, cycloalkyl or aryl wherein each of said alkyl, aryl andcycloalkyl can be unsubstituted or optionally independently substitutedwith one or more moieties which can be the same or different, eachmoiety being independently selected from halo, alkyl, cyano, acyl,hydroxyalkyl, trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-,alkylthio-, alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(O)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl.
 67. A compound of theformula:

or a pharmaceutically acceptable salt, solvate or ester thereof, whereinR¹ is aryl, R²═R³=1-methyl-pyrazol-4-yl, R═H, X is a covalent bond, andR⁴ is a heterocyclyl, wherein said aryl can be unsubstituted orsubstituted with one or more moieties which can be the same or differenteach moiety being independently selected from the group consisting ofhalo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵) and —N(R¹⁴)C(O)R¹⁵,wherein said heterocyclyl can be unsubstituted or optionally substitutedwith one or more independently selected R⁸ groups; R⁶ is H, alkyl,cycloalkyl or aryl, wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁷ is H, alkyl,cycloalkyl or aryl wherein each of said alkyl, aryl and cycloalkyl canbe unsubstituted or optionally independently substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, -alkoxy, —OCF₃, —CF₃, dialkylamino-, alkylthio-,alkylsulfonyl-, dialkylaminosulfonyl-, —NO₂, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, and —C(O)O-heteroaryl; R⁸ is selected fromthe group consisting of halo, alkyl, cyano, —N(R¹⁴R¹⁵), —C(O)—N(R¹⁴R¹⁵),—S(O₂)—N(R¹⁴R¹⁵), —S(O)—N(R¹⁴R¹⁵), —N(R¹⁴)C(O)R¹⁵, —C(O)O-alkyl,—O(CO)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —OR¹⁴, —SR¹⁴,—O—CO—N(R¹⁴R¹⁵)— and —N(R¹⁴)—CO—N(R¹⁴R¹⁵); and R¹⁴ and R¹⁵ can be thesame or different, each being independently selected from the groupconsisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,heterocyclyl, acyl, halo, hydroxyalkyl, trifluoromethyl, —OR⁶, —OCF₃,—N(R⁶R⁷), —SR⁶, —S(O₂)R⁶, —CN, —S(O₂)N(R⁶R⁷) and —NO₂, wherein each ofsaid alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different each moiety beingindependently selected from halo, alkyl, cyano, acyl, hydroxyalkyl,trifluoromethyl, OR⁶, —OCF₃, —CF₃, —N(R⁶R⁷), —SR⁶, —S(O₂)R⁶,—S(O₂)N(R⁶R⁷), —NO₂, —C(O)O-alkyl, —O(CO)O-alkyl, —C(O)O-aryl, and—C(O)O-heteroaryl.
 68. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof.
 69. A compound according to claim 1 or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof in purified form. 70.A pharmaceutical composition comprising a therapeutically effectiveamount of at least one compound of claim 1 or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof, in combination withat least one pharmaceutically acceptable carrier.
 71. The pharmaceuticalcomposition according to claim 76, further comprising one or moreanti-cancer agents different from the compound of claim
 1. 72. Thepharmaceutical composition according to claim 77, wherein the one ormore anti-cancer agents are selected from the group consisting ofcytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide,irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones,tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778123, BMS 214662, Iressa®,Tarceva®, antibodies to EGFR, Gleevec®, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, Vinblastine,Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin,Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Dromostanolone propionate, Testolactone, Megestrolacetate,Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone,Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine,Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole,Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin,Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine,Profimer, Erbitux®, Liposomal, Thiotepa, Altretamine, Melphalan,Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab,C225, Doxil, Ontak, Deposyt, Mylotarg, Campath, Celebrex, Sutent,Aranesp, Neupogen, Neulasta, Kepivance, SU11248, and PTK787.
 73. Amethod of inhibiting one or more cyclin dependent kinases, or treatingone or more diseases associated with a cyclin dependent kinase,comprising administering a therapeutically effective amount of at leastone compound of claim 1 or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof to a patient in need of such inhibition.
 74. Amethod of treating one or more diseases associated with cyclin dependentkinase, comprising administering to a mammal in need of such treatmentan amount of a first compound, which is a compound of claim 1, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof; andan amount of at least one second compound, the second compound being ananti-cancer agent different from the compound of claim 1; wherein theamounts of the first compound and the second compound result in atherapeutic effect.
 75. The method according to claim 73, wherein thecyclin dependent kinase is CDK1.
 76. The method according to claim 73,wherein the cyclin dependent kinase is CDK2.
 77. The method according toclaim 73, wherein the disease is selected from the group consisting of:cancer of the bladder, breast, colon, kidney, liver, lung, small celllung cancer, non-small cell lung cancer, head and neck, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin,including squamous cell carcinoma; leukemia, acute lymphocytic leukemia,chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-celllymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma,hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett'slymphoma; acute and chronic myelogenous leukemia, myelodysplasticsyndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma.
 78. The method accordingto claim 73, further comprising radiation therapy.
 79. The methodaccording to claim 74, wherein the anti-cancer agent is selected fromthe group consisting of a cytostatic agent, cisplatin, doxorubicin,taxotere, taxol, etoposide, irinotecan, camptostar, topotecan,paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil,methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R15777,L778123, BMS 214662, Iressa®, Tarceva®, antibodies to EGFR, Gleevec®,intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard,Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin,Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C,L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol,Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Profimer, Erbitux®, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Ifosfomide, Rituximab, C225, Doxil, Ontak, Deposyt, Mylotarg, Campath,Celebrex, Sutent, Aranesp, Neupogen, Neulasta, Kepivance, SU11248, andPTK787.
 80. A method of inhibiting one or more Checkpoint kinases, ortreating, or slowing the progression of, a disease associated with oneor more Checkpoint kinases, in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of atleast one compound of claim 1 or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof.
 81. A method of treating one or morediseases associated with Checkpoint kinase, comprising administering toa mammal in need of such treatment an amount of a first compound, whichis a compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof; and an amount of at least one secondcompound, the second compound being an anti-cancer agent; wherein theamounts of the first compound and the second compound result in atherapeutic effect.
 82. The method of claim 81, wherein anti-canceragent is selected from the group consisting of a cytostatic agent,cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778123, BMS 214662, Iressa®, Tarceva®, antibodies toEGFR, Gleevec®, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracilmustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine.Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin,Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C,L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol,Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate Leuprolide,Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Profimer, Erbitux®, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Ifosfomide, Rituximab, C225, Doxil, Ontak, Deposyt, Mylotarg, Campath,Celebrex, Sutent, Aranesp, Neupogen, Neulasta, Kepivance, SU11248, andPTK787.
 83. A method of treating, or slowing the progression of, adisease associated with one or more Checkpoint kinases in a patient inneed thereof, comprising administering a therapeutically effectiveamount of a pharmaceutical composition comprising in combination atleast one pharmaceutically acceptable carrier and at least one compoundaccording to claim 1, or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof.
 84. The method according to claim 83, whereinthe Checkpoint kinase is Chk1.
 85. The method according to claim 83,wherein the Checkpoint kinase is Chk2.
 86. A method of inhibiting one ormore tyrosine kinases, or treating, or slowing the progression of, adisease associated with one or more tyrosine kinases, in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of at least one compound of claim 1 or apharmaceutically acceptable salt, solvate, ester or prodrug thereof. 87.A method of treating one or more diseases associated with tyrosinekinase, comprising administering to a mammal in need of such treatmentan amount of a first compound, which is a compound of claim 1, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof; andan amount of at least one second compound, the second compound being ananti-cancer agent; wherein the amounts of the first compound and thesecond compound result in a therapeutic effect.
 88. A method oftreating, or slowing the progression of, a disease associated with oneor more tyrosine kinases in a patient in need thereof, comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising in combination at least one pharmaceuticallyacceptable carrier and at least one compound according to claim 1 or apharmaceutically acceptable salt, solvate, ester or prodrug thereof. 89.The method according to claim 87, wherein the tyrosine kinase isselected from the group consisting of VEGF-R2, EGFR, HER2, SRC, JAK andTEK.
 90. The method according to claim 87, wherein the tyrosine kinaseis VEGF-R2.
 91. The method according to claim 87, wherein the tyrosinekinase is EGFR.
 92. A method of inhibiting one or more Pim-1 kinases, ortreating, or slowing the progression of, a disease associated with oneor more Pim-1 kinases, in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of atleast one compound of claim 1 or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof.
 93. A method of treating one or morediseases associated with Pim-1 kinase, or treating, or slowing theprogression of, a disease associated with one or more Pim-1 kinases,comprising administering to a mammal in need of such treatment an amountof a first compound, which is a compound of claim 1, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof; andan amount of at least one second compound, the second compound being ananti-cancer agent, wherein the amounts of the first compound and thesecond compound result in a therapeutic effect.
 94. A method of treatinga cancer comprising administering a therapeutically effective amount ofat least one compound of claim 1, or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof.
 95. The method of claim 94, whereinsaid cancer is selected from the group consisting of: cancer of thebladder, breast, colon, kidney, liver, lung, small cell lung cancer,non-small cell lung cancer, head and neck, esophagus, gall bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, includingsquamous cell carcinoma; leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkinslymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle celllymphoma, myeloma and Burkett's lymphoma; acute and chronic myelogenousleukemia, myelodysplastic syndrome and promyelocytic leukemia;fibrosarcoma, rhabdomyosarcoma; head and neck, mantle cell lymphoma,myeloma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma,seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
 96. Amethod of treating a cancer, comprising administering to a mammal inneed of such treatment an amount of a first compound, which is acompound of claim 1, or a pharmaceutically acceptable salt, solvate,ester or prodrug thereof; and an amount of at least one second compound,said second compound being an anti-cancer agent; wherein the amounts ofthe first compound and said second compound result in a therapeuticeffect.
 97. The method of claim 96, further comprising radiationtherapy.
 98. The method of claim 96, wherein said anti-cancer agent isselected from the group consisting of cytostatic agent, cisplatin,doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar,topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778123, BMS 214662, Iressa®, Tarceva®, antibodies toEGFR, Gleevec®, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracilmustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine,Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin,Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux®, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225, Doxil, Ontak, Deposyt,Mylotarg, Campath, Celebrex, Sutent, Aranesp, Neupogen, Neulasta,Kepivance, SU11248, and PTK787.